Comparative effectiveness and safety of topical methimazole 5% monotherapy versus combination of Q‐Switched Nd: YAG Laser and topical methimazole 5% in patients with refractory melasma

Melasma is an acquired pigmentary disorder which currently has no definitive treatment. Although topical drugs containing hydroquinone are the basis of treatments, they are usually associated with recurrence. We aimed to evaluate the effectiveness and safety of monotherapy with topical methimazole 5% versus combination of Q‐Switched Nd: YAG Laser and topical methimazole 5% in patients with refractory melasma.


| INTRODUC TI ON
Melasma is an acquired pigmentary disorder, known by macules and patches in color of brown or gray. It mostly affects face and neck; and rarely the upper limbs. Its prevalence is higher in females, youth and people with IV-V Fitzpatrick skin type. 1,2 Excessive concentration of melanin in the cutaneous tissue, which can be a result of melanocytosis or melanogenesis, causes hyperpigmentation and melasma. 3 Genetic predisposition, UV light exposure, hormone therapy, thyroid disease, pregnancy, and medications such as phenytoin are known as the risk factors of melasma. 4,5 Unfortunately, there is still no definitive therapeutic regimen for this disease. Although topical drugs containing hydroquinone are the basis of melasma treatments, they are usually associated with recurrence. Mesotherapy, microdermabrasion, and energy-based treatment modalities (laser therapy) like ultrapulse CO 2 Laser, erbium:YAG laser, and Q-Switched Nd: YAG Laser are the other common therapeutic methods. [6][7][8] Given that the treatment of patients with melasma, particularly resistant-to-treatment cases, is challenging and refractory melasma seems to be resistant to the routine treatments, we aimed to investigate the effectiveness of monotherapy with topical methimazole 5% versus the combination of topical methimazole 5% with Q-Switched Nd: YAG Laser in refractory melasma, which are reported to be effective and well-tolerated in treating melasma patients.

| MATERIAL AND ME THOD
A total of 30 female patients with melasma whom had received at least two common melasma treatments for 3 months (at least) and had no improvement (<25%) were included in this study. Patients with autoimmune diseases, hepatitis, coagulopathy disorders, thyroid diseases treated by drugs like phenytoin, use of tranexamic acid (over the last 1 month), use of tretinoin drugs (over the last 3 weeks), use of topical medications for skin pigmentations (over the last 1 month), hormone therapy (such as taking OCP), anticoagulant agents, laser therapy to treat melasma (over the last 6 months), pregnant or breastfeeding mothers, and allergy (drug reaction) to the therapeutic regimen of the study were excluded.
Patients went under treatment for 12 weeks in a face split method. For each patient, we applied topical methimazole 5% (once a day) on the left half of the face (group 1), and topical methimazole 5% (once a day) with three passes of QSNd: YAG laser (Wavelength: 1064 nm, pulse energy: 750 mJ, fluence: 1.50 J/cm 2 , spot size: 4 × 4 mm, hand piece: fractional, JEISYS company) for six sessions with 2-weeks interval, on the right half of the face (group 2). The patients used topical solution of metimazole 5% every night before sleeping, and at the morning washed it with water. They were also asked to use sunscreen twice a day (at the morning and midday).
The dermatologist responsible for measuring outcomes, and the project partner who is responsible for statistical analysis, were unaware of the grouping and type of medication.
Physician Satisfaction (PS) (by clinical examination) and Patients satisfaction (PtS) was assessed at 4th, 8th, and 12th weeks in form of complete, marked, moderate, slight, no change, and worsening.
The Physician Global Assessment (PGA) and the Patient Global Assessment (PtGA) were assessed as clear, almost clear, mild, moderate, and severe in the initial session, as well as in follow-up sessions at 4th, 8th, and 12th weeks.
In the first session, before starting the treatment process, demographic characteristics of every patient was recorded. PGA and mMASI score were also evaluated. Hyperpigmented lesions in patient's facial region were photographed by a digital camera (Canon EOS). Then, in the follow-up sessions (4th, 8th, and 12th weeks), the extent and amount of pigmentation was compared to the first session and the mentioned indexes were re-evaluated. Objective evaluation was based on improving the intensity of skin pigmentation by viewing serial images taken from hyperpigmented lesions (photo-documented). Modified MASI (Melasma Area and Severity Index) score was used to quantify and measure the clinical severity of hyperpigmentation of lesions in patients. We used the TSQM (treatment satisfaction questionnaire for medication) for evaluating side effects, efficacy, and the harmlessness of the medications and the level of patient satisfaction with the treatment process.
After treatment, patients were followed up for 12 weeks.

| Statistical analysis
Normality of data were checked before selection of parametric tests.
Due to the normality of the data, independent T-test was used to compare PtGA and PtS at any time, and repeated measurement test was used to evaluate the changes over time. Fisher's Exact test was used to compare the frequency and type of complications between the two groups. p Value of <0.05 was considered as statistically significant. PtGA and PtS did not significantly differ between the two groups at any time (p-value > 0.05). Time factor was effective in both groups; meaning that PtGA and PtS were significantly improved over time in both groups, but this rate was not significantly different between the two groups (p-value > 0.05) ( Table 1).

| RE SULT
The independent T-test showed that PGA did not significantly differ between the two groups at any time (p-value > 0.05). PS in group 2 was better than group 1 at 4th, 8th, and 12th weeks, and it was statistically significant (p-value < 0.05) (Figures 1-4). Repeated measurement test showed that time factor was effective in both groups and PGA and PS were significantly improved in both groups over time. There was an interaction between time and the groups, so that improvement rate of PGA in group 2 was better than group 1 over time and this difference was statistically significant (pvalue < 0.001) ( Table 2).
Changes of mMASI score between the two groups was not significantly different (p > 0.05). Repeated measurement test showed that the time factor was effective in both groups and mMASI score in both groups was significantly improved over time, but this rate was not different between the two groups (p > 0.05) ( Table 3).
There was no significant difference in the frequency and type of complications between the two groups (p > 0.05) ( Table 4).

| DISCUSS ION
Laser therapy helps to reduce the activity of melanocytes and melanin production by targeting only the melanosomes, without destroying the melanocytes. [9][10][11][12][13] Methimazole is an oral anti-thyroid drug. Its topical form can help process of skin depigmentation. 14,15 According to the best of our knowledge, there is no study comparing the efficacy of methimazole with Q-switched laser therapy in melasma treatment. We evaluated the effectiveness of topical methimazole versus its combination with laser therapy.

Atefi et al. investigated about the effectiveness of topical
Methimazole 5% against topical hydroquinone 2% for treating melasma patients, in a double-blind randomized trial. Fifty-eight female patients with melasma were treated for 8 weeks. In this study, improvement with topical methimazole was significantly better than hydroquinone (p < 0.05). 16 Malek et al. studied on the efficacy of topical Methimazole 5% in treating two melasma patients which were resistant to hydroquinone 4%. Topical methimazole 5% was F I G U R E 1 Group 2, comparing before and after treatment.
F I G U R E 2 Group 2, comparing before and after treatment.
applied once a day for 8 weeks; which resulted in significant improvement. 14 Yenni et al. investigated the effectiveness of topical methimazole 5% in comparison with topical kojic acid 4% in 45 patients with melasma, using a face-split technique. According to the mMASI score, methimazole was more effective than kojic acid. PtS improvement rate in the methimazole group was also better than the kojic acid group, and it was statistically significant (p-value < 0.05). 17 In the present study, we also observed the efficacy of topical methimazole 5% in refractory melasma.

Choi et al. investigated about the effectiveness of Q-switched
Nd:YAG laser for treating Asian patients with melasma. Ten sessions of laser therapy were applied on 40 patients with III-IV Fitzpatrick skin type, with interval of 1 week. Evaluating the patients' improvement was based on the mMASI score and PGA.
In their study Q-switched Nd: YAG laser was found to be effective. 18 Sim et al. studied the effectiveness of 1064-nm Q-switched F I G U R E 3 Group 1, comparing before and after treatment.

F I G U R E 4
Group 1, comparing before and after treatment.

TA B L E 2
Mean and standard deviations of PGA and PS in two groups over time In our study, Q-switched Nd:YAG laser was found to be effective in the treatment of melasma.

| CON CLUS ION
Combination therapy with topical methimazole 5% and Q-Switched Nd: YAG laser is an effective method for the treatment of refractory melasma.

| Limitations
Although we report topical methimazole 5% and Q-Switched Nd: YAG laser as an effective combination therapy in treating refractory melasma, our study has limitations of small size and short follow-up duration. Larger studies are necessary to confirm our observations.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C S S TATEM ENT
The study was approved by the ethical committee of Mazandaran University of Medical Sciences. Ethical approval number: IR.MAZUMS.REC.1398.1343.

I N FO R M ED CO N S ENT
Written consent was obtained from all the patients.