A combination treatment of drug‐laser‐photon for melasma: A retrospective study of clinical cases

Abstract

Background

Combinational therapy such as taking tranexamic acid while using laser treatment has been proved potential efficacy by many experiments. However, there is few research which contains large samples and consistent observations.

Objective

We evaluated clinical efficacy and safety of a new systemic treatment of drug‐laser‐photon therapy.

Methods

Retrospective and randomized investigator‐blinded study of 75 patients with mixed type melasma was analyzed. At each visit, standardized photographs were taken using VISIA. Modified melasma area and severity index (mMASI) scores were marked using photographs by two dermatologists.

Results

The mMASI score decreased significantly from 6.92 to 3.84 after the treatment. The VISIA analyze right cheek data shows: Spots (from 49.67 ± 3.43 to 56.09 ± 3.31), UV spots (from 41.39 ± 24.45 to 44.56 ± 25.86), and Brown spots (from 23.97 ± 17.89 to 28.16 ± 21.28) are statistically increased (p = 0.035, p = 0.018, p = 0.07). All patients feel varying degrees of improvement, about 10.17% felt very much improved, 30.51% felt much improved (51%–75%), 45.76% felt moderately improved (26%–50%), and 13.56% felt little improved (1%–25%).

Limitations

This study was no control group.

Conclusion

The efficacy and safety profile of the combination of drug‐laser‐photon therapy systemic treatment in melasma patients has been proved. It has potential possibility to become a new, reliable, widely suitable therapy strategy.

INTRODUCTION

Melasma is a common post-escity pigmentation disorder, characterized by irregular pigmentation on both sides. It has more likely to occur in darker-skinned Asians and Latin America, and it prefers female than males. Genetics, sun exposure, and hormones (e.g., pregnancy, COC) are reported to be possible pathogenic factors. Its lesions have an important visual impact causing psychosocial stress and impairing quality of life in patients. High incidence currently no effective cure and high recurrence rate made melasma a huge challenge in plastic surgery. No treatment has been shown to be the best choice, but combination therapy should be preferred.

Hydroquinone was once the “golden standard” for the treatment of melasma, but its clinical application was limited by its many complications. On August 29, 2006, the U.S. Food and Drug Administration (FDA) issued a ban on over-the-counter sales of cosmetics containing hydroquinone, after that, hydroquinone has already been prohibited gradually in Japan, the European Union, Australia, and China. Recently, the efficacy of tranexamic acid (TA) in treating melasma has been discovered and proved by more and more researches which is quite popular with Japanese and Korean. TA is an inhibitor of the activation of plasminogen, FDA-approved, its indications include excessive menstruation, reduce or prevent hemophilia patients tooth-pulling bleeding, the former dose is 3900 mg, the latter is 30–40 mg/kg, which is far from the regular oral dose of melasma treatment (usually 250 mg, bid). TA acts as a lysine derivative that inhibits the activation of plasminogen by blocking lysine binding sites on the cell surface of the plasminogen, thereby reducing the production of newly vessels and the rising in melanin caused by the increase of arachidonic acid. There may be other possible mechanisms: TA interferes the interconnection between melanocytes and keratinocytes, reducing the transport of melanin particles to cells. Scientists have found that injecting TA into an animal model of ultraviolet-induced pigmentation does not affect the quantities of melanocytes, so it may inhibit melanin's production and expression by affecting the function of melanocytes. TA can reduce the level of VEGF and ET-1, thus reducing angiogenesis in melasma. Its application in the treatment of melasma was first reported in 1979. Effectiveness and safety have been verified by many researches, until now, no serious adverse events were reported in all oral TA tests. Studies have shown that when TA are used as monotherapies, negative results occur occasionally, but when combined with other treatments based on improved pigmentation, the efficacy increases. Combinational therapy has been tried out, especially with laser therapy. Hypodermic injection or topical application of TA combined with 1064-nm QS-Nd: YAG laser has been proved effective. 1064-nm QS-Nd: YAG laser and IPL have their own advantages and limitations, the combination of the two works better.

This combination does not require multiple weekly irradiation of the 1064-nm QS-Nd: YAG laser (generally more than 10 times in examination), which benefits the patients, also it can reduce the risk of rebound pigmentation caused by IPL. Firstly, using IPL to remove epidermal pigments quickly, then inhibiting the reactivation of melanosomes by subsequent 1064-nm QS-Nd: YAG laser, significant clinical effects appear just after 5 times. Cho et al. and Na et al. proposed the “first IPL, subsequent 1064-nm QS-Nd: YAG laser” strategy and adding oral-taking TA during and after the treatment, they found an improvement in the outcome. But whether to take TA before laser treatment still remains unexplored. According to existing research, we put forward a new systemic treatment of drug-laser-photon therapy and applied in clinic. This article reviewed clinical cases of melasma of all skin types between 2018 and 2020 in the Fourth Affiliated Hospital of Zhejiang University to figure out the safety and effectiveness.

MATERIALS AND METHODS

Type of study

This was a retrospective, randomized investigator-blinded study performed in a single center between January 1, 2018, and December 31, 2020.

Participants/patients

All 75 subjects were consented to use their clinical photographs for academic and research purposes. The diagnosis of melasma is based on clinical diagnosis. Because our patients are around 40 years old, we need to distinguish it from senile plaques.

Cases selection (inclusion/exclusion criteria): According to hospital records, the observation objects have been excluded pregnancy or lactation, history of thrombosis, coagulation, and psychological disorders. Only one patient (Huang Wei), who had historical records, showed that he had sleep disorders (diagnosed in March 2019). All patients were instructed to avoid sun exposure and put on a broad-spectrum sunscreen, during and after treatments.

Technique

Drug-Laser-Photon Therapy Systemic Treatment: (a) For newly diagnosed patients, taking tranexamic acid tablets (Transamin) 1000 mg/day for the first month, and reduce the dosage to 500 mg/day until next visit; External use of “Tranexamic acid essence cream” (Med Care®) in daytime and/or “tranexamic acid cataplasm” (EasyFace®) at night. (b) when second visit (usually 1.5–2.5 months after the first visit), using the Revlite SI c10 once a fortnight, at least ten times in a row. The IPL (harmonyxl) can be added in the process according to the condition of melasma (1–2 times, usually at the time when the symptom is improved). During the laser treatment, if the spots get worse, immediately continue to take tranexamic acid. The paraments are recorded in Table .

TABLE 1 Lights parameters

Lights (nm)	Fluence (J/cm2)	Pulse width	Spot (mm)	Pulse delay
500–600	7.4–7.6	12 ms	10 × 30	12 ms
550–650	8.6–9.0	12 ms	10 × 30	12 ms
1064	2.5–2.6	–	8–9.8	–

The entire face was covered as a treatment field. The laser fluence was adjusted based on patients' response to the previous treatment. No topical anesthesia and pre-procedure processes were used. The treatment endpoint of IPL is when observed mild pigmentation darken and floating, 1064-nm QS-Nd: YAG laser end with the skin micro-hot palpation and reddish.

Two ice packs are routinely given after treatment, usually applied within 30 min, if a severe burning sensation or a redder treatment area appear, patients were asked to apply ice for half an hour to an hour.

CLINICAL ASSESSMENT

Objective evaluation

Photography is performed at the first visit before any treatment and every follow-up visit before laser treatment. Standardized photographs were taken from the front and side of both cheeks using VISIA® (Canfield Scientific, Inc.). Complexion Analysis imaging system with the same fluorescent light and background, and fixed camera parameters, angle, flash, and distance, but we only analyze and compare the database in the right cheek.

An objective assessment was evaluated by using VISIA (Canfield Scientific, Inc.). Complexion Analysis imaging system using its own database, which included eight parameters including spots, wrinkles, texture, pores, ultraviolet (UV) spots, brown spots, red areas, and porphyrins on the forehead and both cheeks. A higher VISIA score indicated better skin condition.

Two qualified plastic surgeons score randomly shuffled photos under the criterion of modified melasma area and severe index (mMASI), and the final scores were averaged.

The mMASI is explained as follows:

The area (A) of melasma involvement is graded from 0 to 6:

• 0 = no involvement.
• 1 = less than 10% involvement.
• 2 = 10%–29% involvement.
• 3 = 30%–49% involvement.
• 4 = 50%–69% involvement.
• 5 = 70%–89% involvement.
• 6 = 90%–100% involvement.

• The degree of pigmentation (P) graded from 0 to 4:

• 0 = absent.
• 1 = slight.
• 2 = mild.
• 3 = marked.
• 4 = maximum.

• mMASI score = 0.3 A (F) P (F) + 0.3 A (RMR) P (RMR) + 0.3 A (LMR) P (LMR) + 0.1 A (M) P (M)

Legend: A, area score; P, pigmentation score; F, Forehead; RMR, Right Malar; LMR, Left Malar; M, mandibular area.

Subjective evaluation

Record all skin discomforts and adverse drug events occurred in treatment duration. Patients were also asked to self-evaluate the degree of improvement comparing before and after laser therapy with the same scale rated as five level.

Safety assessments

Any possible complications and side effects (erythema, edema, burning, petechiae, acute urticaria, post-inflammatory hypopigmentation, and hyperpigmentation) were recorded at each visit.

Statistical analysis

All the statistical analyses were performed using IBM®SPSS® software, version 21 (IBM Corporation). Statistical significance was defined as p < 0.05.

RESULTS

Demographic characteristics

Demographic analysis is shown in Table . A total of seventy-five patients were composed of seventy-three females and two males. The mean age of all the patients was 39.33 years old (range from 17 to 55).

TABLE 2 Patients' demographic data

Variable
Age, years, mean ± SD	39.33 ± 7.89
Sex, n (%)
Female	73 (97.33%)
Male	2 (2.67%)

Treatment efficacy assessments

The efficacy of the treatment was assessed according to mMASI scoring, showing that the mMASI score decreased significantly from 6.92 to 3.84 after the treatment (Table ). Database on the VISIA about the right cheek shows the following changes: spots (from 49.67 ± 3.43 to 56.09 ± 3.31), UV spots (from 41.39 ± 24.45 to 44.56 ± 25.86), and Brown spots (from 23.97 ± 17.89 to 28.16 ± 21.28) are statistically increased (p = 0.035, p = 0.018, p = 0.07; Table ; Figures  and ), whereas red areas, wrinkles texture pores, and porphyrins do not show the differences (p > 0.05) at the same time.

TABLE 3 Mean modified melasma area and severity index after treatments

Initial mMASI	Final mMASI	% reduction	p-value (Initial vs. final)
6.92 ± 1.56	3.84 ± 1.71	44.54	<0.01

TABLE 4 VISIA percentage data

	Initial (%)	Final (%)	p
Spots	49.67 ± 3.43	56.09 ± 3.31	0.035
UV spots	41.39 ± 24.45	44.56 ± 25.86	0.018
Brown spots	23.97 ± 17.89	28.16 ± 21.28	0.007
Red areas	33.68 ± 24.23	35.56 ± 26.24	0.468
Wrinkles	39.09 ± 27.28	43.55 ± 27.17	0.152
Texture	68.04 ± 26.31	69.92 ± 24.40	0.373
Pores	58.00 ± 34.60	60.48 ± 34.30	0.189
Porphyrins	78.32 ± 24.66	82.05 ± 21.59	0.079

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Among the 75 patients, 23 patients have continuous imaging records. We tracked and analyzed their 4 consecutive records within a year (one month apart each time). In the field of brown spots and UV spots, the difference between the first record and the third, fourth, second and fourth, and the third and fourth data is statistically significant (Table ), which may to some extent indicate that the improvement of the melasma is related to the treatment time and the improvement of melasma has a time cumulative effect.

TABLE 5 p-value between different groups in Brown spots

Compare groups	p-value
First–second	0.254
First–third	0.042
First–forth	0.005
Second–third	0.397
Second–forth	0.005
Third–forth	0.024

We let patients evaluate the treatment effect themselves according to the criterion as following: Very much improved (76%–100%), Much improved (51%–75%), Moderately improved (26–50%), Little improved (1%–25%), Not improved or even worse, and finally, a total of 59 valid data are included (Table ).

TABLE 6 Patient self-Assessment of degree of melasma improvement (n = 59)

Improvement of melasma	n (%)
Very much improved (76%–100%)	6 (10.17)
Much improved (51%–75%)	18 (30.51)
Moderately improved (26%–50%)	27 (45.76)
Little improved (1%–25%)	8 (13.56)
Not improved or even worse	–

Typical case

We pick up 3 cases which is improved conspicuously out of all the participates and show their photos as following (Figures ).

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Safety assessments and follow-ups

Due to factors such as patient migration, finally we successfully followed up 59 patients for one month by telephone, and according to the self-assessment survey (Table ), all patients reported varying degrees of improvement compared to before treatment.

Skin discomfort: Some patients happen to have redder skin immediately after laser treatment and will be slightly swollen within two or three days.

Adverse drug reactions: Because tranexamic acid is a small-dose hemostatic drug, female patients are instructed to stop the drug during menstrual period and continue to take it when the menstrual period finished. Individual patients reported having stomach discomfort after taking the drug, so they are recommended to take it after meals. No other adverse reactions were reported.

Approximately 10% of patients report orally that they found the spots have recurred or got slightly worse.

DISCUSSION

1064-nm QS-Nd: YAG laser therapy is believed as an effective method in treating melasma especially in dark skin types, and it is widely used in clinic. It can reduce melanin particles; however, only a temporary improvement observed when treating Asians. Common complications include hypopigmentation, recurrence of melasma, and rebound hyperpigmentation.

IPL is a potential treatment method, which is an effective treatment option for removing melanocyte lesions, especially epidermal lesions. However, melasma is identified as a deep pigmented lesion. In addition, because of its powerful energy, PIH may be more likely to occur. As the concern mentioned above, the strategy we proposed that moderate to severe melasma patients apply 1064-nm QS-Nd: YAG laser firstly and add IPL treatment when symptom is improved is thoughtful.

Many combination therapies emerged one after another based on the idea that monotherapy is not as effective as combination with other therapy, such as oral TA combined with 1064-nm QS-Nd: YAG laser, 1064 combined with IPL, and the combination of the three. The facts have also proved that the combined treatment is better than single treatment. Scientists found that the destruction of the skin barrier can also lead to recurrence, so we recommend that patients use medical dressings to protect the skin barrier. In summary, the comprehensive treatment we proposed is a integrated one.

Zhong indicated that the expression of type III procollagen was most significant at 2 weeks after irradiation, and the best clinical effect could be obtained 4 weeks after the irradiation. A meta-analysis reveals that one or two weekly intervals can maximize treatment effects and reduce the incidence of adverse events. So, we set up the laser treatment interval as 2 weeks.

Also, there is currently no conclusion on the optimal oral dose of TA, which may be related to the selected treatment method, but at least it is confirmed that 500 mg of TA per day is safe and effective. Natalia et al. listed oral TA 250 mg bid as the first-line treatment. Topical therapy with a HQ and retinoid-based product should be first line for a minimum of 3 months with the addition of oral tranexamic acid at 250 mg bid if no contraindication. Moreover, In a recently study, Shin et al. found that those treated for 8 weeks with 750 mg/day TXA enhanced the efficacy of low-fluence QS Nd:YAG (two sessions with a 4-week interval; laser settings were not specified).

There are several indicators in VISIA; we mainly focus on Brown spots and UV spots, because these indicators are closely related to melasma. In the above results, spots, Brown spots, and UV spots decrease significantly, and mMASI have decreased. This strongly proves that the comprehensive treatment we proposed is effective, and the treatment effect improves over time during the treatment cycle. Studies have shown that there was a significant relationship between the number of vessels and pigmentation in melasma. The expression of VEGF was significantly increased in melasma and TA as a hemostatic agent can reduce the number of blood vessels, and 1064-nm QS-Nd: YAG laser therapy has the same function theoretically, but we did not find the improvement on red areas (Table ). Most patients treated with laser will also have the benefits of improved skin texture or brightening skin color, but in this article, the value of wrinkle (Table ) is not statistically significant.

Only 10% of patients were observed relapse, which may can be accounted for short follow-up time (1 month). The recurrence of melasma is usually happen at 3 months after laser treatment. In addition, almost all patients will eventually relapse after stopping the corresponding treatment. Melanocyte activation and skin barrier disruption may be related to the high relapse rate of melasma. A recently published study demonstrated that when treated with microneedling and non-ablative Q-switched Nd:YAG laser, greater improvement in melasma severity and lower recurrence rate occurs, compared to Q-switched Nd:YAG laser monotherapy.

Although some predecessors have used VISIA data for analysis, the VISIA percentiles have not become a recognized scoring system. In this article, compared with absolute scores, percentages can exclude the impact of different skin types. Moreover, when using VISIA analysis, due to the need to manually adjustment, there will inevitably be human error, and the scope of each image analysis cannot be completely consistent. In addition, the slight changes in the patient's expression at each photograph taking may affect the value of wrinkles. Those uncontrollable error may be responsible for why it cannot become the gold standard, but it still has its value for reference.

The following discusses the limitation in the study: This is a clinical retrospective study limited to 75 cases, other similar clinical cases cannot be presented, and the number of samples is insufficient. Due to the migration of the patient's lifestyle, we cannot follow-up each case for more than 1 month. Due to the inconvenience of telephone follow-up, it is not possible to objectively quantify the recurrence of stains after the end of treatment, and it may be inaccurate to rely solely on patient self-evaluation. This study was a retrospective chart review of the treatments, and there was no control group.

AUTHOR CONTRIBUTIONS

All authors have read and approved the final manuscript. Li, Y., Shao, W., and Wang, S. performed the research. Wang, X., Tan, W., and Xue, Y. designed the research study. Chen, L. and Wu contributed essential reagents or tools. Fang, Q., Hu, Y., and Zhao, W. analyzed the data. Li, Y. and Shao, W. wrote the paper.

ACKNOWLEDGMENTS

This work was supported by grants from National Natural Science Foundation of China (No. 81671918 and 81372072), Zhejiang Provincial Medical and Healthy Science Foundation of China (No. 2019ZD028), and National Key Research Program of China (2016YFC1101004). This study was approved by the Fourth Affiliated Hospital of Zhejiang University.

CONFLICT OF INTEREST

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

ETHICAL APPROVAL

Our study complied with the Declaration of Helsinki, international ethical guidelines such as GCP and ICH-GCP, as well as relevant domestic laws and regulations, and was approved by the Human Research Ethics Committee of the Fourth Affiliated Hospital of Zhejiang University School of Medicine. The ethical approval code is K2022151.

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