Treatment of Melasma in Asian Skin Using a Fractional 1,550-nm Laser: An Open Clinical Study HYOUN SEUNG LEE, MD, CHONG HYUN WON, MD,y DONG HUN LEE, MD,zyz JEE SOO AN, MD,zyz HANG WOOK CHANG, MD,J JONG HEE LEE, MD, KYU HAN KIM, MD,zyz SOYUN CHO, MD, AND JIN HO CHUNG, MDzyz BACKGROUND Melasma is a common hyperpigmentation disorder that can cause refractory cosmetic disfigurement, especially in Asians. Fractional photothermolysis (FP) has been reported to be effective for the treatment of melasma, despite small study populations and short follow-up periods. OBJECTIVE To evaluate the efficacy and safety of FP for the treatment of melasma in Asians. PATIENTS AND METHODS Twenty-five patients with melasma received four monthly FP sessions and were followed up to 24 weeks after treatment completion. Efficacy was evaluated using objective and subjective ratings, Melasma Area and Severity Index (MASI), melanin index tracking, and skin elasticity measurements. RESULTS Investigators observed clinical improvements in 60% and patients in 44% at 4 weeks after treatment, but the figures decreased to 52% and 35%, respectively, at 24 weeks after treatment. Mean MASI scores decreased significantly from 7.6 to 6.2. Mean melanin index decreased significantly after the first two sessions, but it relapsed slightly in subsequent follow-ups. The treatment did not alter skin elasticity. Hyperpigmentation was observed in three of 23 subjects (13%). CONCLUSION Treatment of melasma with FP led to some clinical improvements, but it was not as efficacious as previously reported at 6-month follow-up. We recommend judicious use of FP for the treatment of melasma in Asian skin because of its limited efficacy. The authors have indicated no significant interest with commercial supporters. M elasma is a common acquired hypermelanosis characterized by irregular light- to darkbrown macules and patches on sun-exposed areas of the skin. It is common in Asian and Hispanic women.1 In spite of its high prevalence, its pathogenesis has not been clearly defined. Numerous treatment options, including topical agents such as hydroquinone, retinoic acid, and chemical peels, have been tried, but most of them have therapeutic limitations.2–6 A few kinds of ablative laser resurfacing, including pulsed carbon dioxide laser and erbium-doped yttrium aluminum garnet laser resurfacing, have been reported successful, but these require significant downtime and have risks of significant complications.7–9 Fractional resurfacing laser devices have recently been introduced for the treatment of various skin conditions such as melasma, freckles, pigmentation, facial rhytides, surgical scars, and acne scars.10–12 Fraxel laser (Solta Medical, Inc., Hayward, CA) treatment is one of the mostly widely used fractional photothermolysis (FP) techniques in Korea and has been applied effectively for the treatment of wrinkles, photodamaged skin, acne scars, and dyschromia.13–15 Some pilot studies have showed the Gowoonsesang Dermatology Clinic, Seoul, Korea; yDepartment of Dermatology, Asan Medical Centre, College of Medicine, University of Ulsan, Ulsan; zDepartment of Dermatology and yLaboratory of Cutaneous Aging Research, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea; zInstitute of Dermatological Science, Seoul National University, Seoul, Korea; JAmi Clinic, Seoul, Korea; Department of Dermatology, Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea & 2009 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2009;35:1499–1504 DOI: 10.1111/j.1524-4725.2009.01264.x 1499 F R A C T I O N A L P H O T O T H E R M O LY S I S F O R M E L A S M A effectiveness of FP in melasma, but the study populations were small, and the follow-up periods were short.16,17 Thus, its therapeutic efficacy and safety for larger populations with Asian skin have not been well investigated. We postulated that FP could be a treatment modality for melasma, especially in patients with darker skin. The aim of this study was to evaluate the efficacy and safety of fractional photothermolysis for the treatment of melasma in Asian patients. Patients and Methods Outcome measures included objective and subjective ratings and quantitative determination of melanin indices (MIs) and erythema indices (EI) using a narrow-band reflectance spectrophotometer (DermaSpectrometer, Cortex Technology, Hadsund, Denmark) and of skin elasticity using a noninvasive in vivo suction skin elasticity meter (Cutometer MPA 580, CK Electronics, Ko¨ln, Germany). To quantify the changes in pigmentation after treatment, the Melasma Area and Severity Index (MASI) was used for clinical assessment. According to the MASI score determined by Kimbrough-Green and colleagues,18 the whole face is divided into four areas: the forehead, right malar, left malar, and chin, corresponding to 30, 30, 30, and 10% of the total face area, respectively. The grade of melasma severity was determined according to three variables: the percentages of total area involved, on a scale of 0 (no involvement) to 6 (90–100% involvement); darkness, on a scale of 0 (absent) to 4 (maximum); and the homogeneity of hyperpigmentation, on a scale of 0 (minimal) to 4 (maximum). The MASI was then calculated according to the following equation: Twenty-five women with clinical diagnosis of melasma were recruited for the 36-week prospective open study. Exclusion criteria included pregnant or nursing women, the use of hydroquinone, topical or systemic treatment with vitamin A analog including tretinoin, the use of a topical bleaching agent within 2 months before the study, a history of laser treatment or chemical peeling on facial lesion within 6 months before the study, and the use of contraceptive pills at the time of the study or in the preMASI = 0.3 (DF 1 HF)AF 1 0.3 (DMR 1 HMR)AMR vious 6 months. This clinical study was performed in 10.3 (DML1HML)AML 1 0.1(DC 1 HC) AC, where accordance with the Declaration of Helsinki (1975) D is darkness, H is homogeneity, A is area, F is and was approved by the Institutional Review Board forehead, MR is right malar, ML is left malar, and of Seoul National University Hospital. We explained C is chin. the procedures, risks, benefits, potential complications, and side effects of the procedure to all subjects, A high MASI score correlates with severe hyperpigand written informed consent was obtained from mentation. Safety evaluations were performed at each patient before commencement of this study. each follow-up visit, and any reported adverse effects Four sessions of FP treatment were performed on were recorded. each subject. After 1 hour of occlusive application of topical anesthetic cream (eutectic mixture of lidoFor statistical analysis, data obtained at each visit caine and prilocaine, AstraZeneca, Wilmington, were compared with baseline data using the WilDE), the involved area of the cheeks was irradiated coxon signed rank test in SPSS software (version with a 1,550-nm erbium-doped FP laser (Fraxel la12.0, SPSS Inc., Chicago, IL). Data are expressed as ser) at a fluence of 15 mJ/microthermal zone (MTZ) means 7 standard errors, and po.05 was considered and a density of 125 MTZ/pass with eight passes. to be statistically significant. Follow-up evaluations were made at 4-week intervals during the 12-week treatment period and Results at 4 weeks and 24 weeks after the final session Twenty-five subjects with facial melasma (Fitzpat(total study duration, 36 weeks from treatment rick skin type III or IV) were enrolled in this study. commencement). 1500 D E R M AT O L O G I C S U R G E RY LEE ET AL Figure 1. Clinical appearance of a 49-year-old patient with melasma during the study. Their ages ranged from 32 to 53 years (mean 7 SD age was 40.6 7 6.3). All patients completed the 16-week follow-up (4 weeks after the final session), but two subjects were lost to follow-up by the 24-week posttreatment follow-up. Figure 1 shows serial photographs of a representative patient with melasma during the study. Four weeks after the final treatment session, the global assessment of melasma improvement by dermatologists was as follows; of 25 patients, six (24%) were evaluated as definitely improved, 15 (60%) as improved, nine (36%) as slightly improved, 10 (40%) as no change, and none (0%) as aggravated. Twenty-four weeks after treatment completion, four of 23 patients (17.4%) were assessed as definitely improved, eight (34.8%) as slightly improved, eight (34.8%) as stationary, and three (13%) as aggravated (Figure 2). Figure 2. Investigators’ global assessment of changes in melasma severity. The patients’ subjective global assessment of melasma improvement at 4 weeks after the final session was as follows; of 25 patients, two (8%) graded their skin lesion as definitely improved, nine (36%) as slightly improved, 11 (44%) as stationary, and three (12%) as aggravated. At 24 weeks after treatment completion, eight of 23 patients (34.8%) 35:10:OCTOBER 2009 1501 F R A C T I O N A L P H O T O T H E R M O LY S I S F O R M E L A S M A increase subsequently (Figure 4). FP-induced decreases in EI and MI scores as a function of time indicate laser-induced improvement in vascularity and melanin turnover.19 Skin elasticity as measured using the Cutometer showed no remarkable changes during or after FP treatment (data not shown). Figure 3. Patients’ subjective global assessment of changes in melasma severity. rated their skin lesion as slightly improved, 11 (47.8%) as stationary, and 4 (17.4%) as aggravated because of postinflammatory hyperpigmentation (Figure 3). Mean MASI scores decreased from 7.6 7 0.7 (range 3.2–14.7) at baseline to 6.2 7 0.5 (range 1.8–10.2) at 36 weeks (p = .03, Wilcoxon signed rank test), concurring with the improvement of melasma rated by physicians and patients. FP-treated melasma lesions showed a significant decrease in mean MI after the first two sessions (p = .02 and p = .01, respectively, vs baseline) but a slight increase afterwards in MI (Figure 4). EI also decreased significantly after the first session (p = .004 vs baseline) but showed a gradual Treatment-related pain was well tolerated with topical anesthesia. Transient local swelling on the treated area, long-lasting (44 weeks) erythema, and hyperpigmentation were reported as adverse events, but no patient dropped out of the study because of these adverse events. At the end of the study, hyperpigmentation was partially observed in three of 23 subjects (13%). Discussion Melasma is a common dermatologic condition in dark-skinned women, but currently available conventional treatments have limited value.20 Given the high incidence of postinflammatory hyperpigmentation and unpredictable efficacy, laser treatment for the treatment of melasma has not been recommended routinely.21 Recently developed FP techniques have been known to be used effectively for the treatment of wrinkles, photodamaged skin, acne scars, and dyschromia.13–15 There are preliminary Figure 4. Changes in melanin indices and erythema indices during the study. (A) Mean melanin index showed a significant decrease from baseline to week 8 (4 weeks after 2nd session) but a slight increase afterwards. (B) Mean erythema index also exhibited a temporary but significant decrease at week 4. a.u., arbitrary unit. Error bars indicate standard errors of the means. po.05 versus baseline. 1502 D E R M AT O L O G I C S U R G E RY LEE ET AL reports on the effectiveness of FP on melasma as well.16,17 Rokhsar and Fitzpatrick16 treated 10 female patients with recalcitrant melasma using 1,535nm and 1,550-nm Fraxel lasers (6–12 mJ/MTZ with 2,000–3,500 MTZ/cm2) at 1- to 2-week intervals. The physicians’ assessment at 3-month follow-up revealed that six patients achieved 75% to 100% clearing and three had less than 25% improvement. Patients’ evaluations were in good agreement with physicians’. In the present study, we demonstrated the efficacy and safety of FP for the treatment of melasma in Asian women. At 4 weeks after treatment completion, a physician assessed 60% of patients as improved, and 44% of subjects assessed themselves as improved, although these improvements showed a slight decline subsequently, which resulted in 52.2% and 34.8%, respectively, assessed as improved 24 weeks after treatment. In addition, although MI revealed a significant improvement after the first two sessions, it deteriorated after the third session (12 weeks after commencement of the study) and plateaued in subsequent follow-ups. Recently, new insights into the pathogenesis of melasma have been suggested, based on the comparison of histological characteristics between lesional and nonlesional skin.22–24 These studies indicate that pathologic dermal changes such as altered fibroblasts or greater vascularity are implicated in the pathogenesis of melasma.22–24 The so-called ‘‘melanin shuttle function’’ and remodeling of the underlying pathologic dermis below melasma lesions suggested the possible mechanism of FP for the treatment of pigmentation.25 Melanin shuttle was proposed based on the observation that some dermal material is incorporated into the microepidermal necrotic debris and shuttled up the epidermis to be exfoliated through the stratum corneum after FP treatment.25 Some positive clinical results after FP on pigmentation16,17 might favor this suggested mechanism. In this respect, the results of our study suggest that, in some patients, the depth affected by FP appeared not to be deep enough to cause dermal remodeling to suppress the activation of melanocytes, and the elimination of melanin pigment by melanin shuttle occurred temporarily, leading to reappearance of melanin after the third treatment. The rebound of MI during and after the treatment period supports these assumptions. In conclusion, FP affords a new treatment modality for melasma, but the therapeutic efficacy of FP in our study did not differ significantly from that of conventional treatments,4,8,20,21 in contrast to previously published overly optimistic results. More studies are needed to define the exact place of FP in the treatment of melasma. References 1. Sanchez NP, Pathak MA, Sato S, et al. Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J Am Acad Dermatol 1981;4:698–710. 2. Griffiths CE, Finkel LJ, Ditre CM, et al. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol 1993;129:415–21. 3. Grimes PE. The safety and efficacy of salicylic acid chemical peels in darker racial-ethnic groups. Dermatol Surg 1999;25:18–22. 4. Haddad AL, Matos LF, Brunstein F, et al. A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma. Int J Dermatol 2003;42:153–6. 5. Khunger N, Sarkar R, Jain RK. Tretinoin peels versus glycolic acid peels in the treatment of melasma in dark-skinned patients. Dermatol Surg 2004;30:756–60; discussion 60. 6. Sarkar R, Kaur C, Bhalla M, et al. The combination of glycolic acid peels with a topical regimen in the treatment of melasma in dark-skinned patients: a comparative study. Dermatol Surg 2002;28:828–32; discussion 32. 7. Goldberg DJ. Benign pigmented lesions of the skin. Treatment with the Q-switched ruby laser. 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Facial Plast Surg Clin North Am 2007;15:229–37, vii. 14. Lee HS, Lee JH, Ahn GY, et al. Fractional photothermolysis for the treatment of acne scars: a report of 27 Korean patients. J Dermatol Treat 2008;19:45–9. 15. Wanner M, Tanzi EL, Alster TS. Fractional photothermolysis: treatment of facial and nonfacial cutaneous photodamage with a 1,550-nm erbium-doped fiber laser. Dermatol Surg 2007;33:23–8. 16. Rokhsar CK, Fitzpatrick RE. The treatment of melasma with fractional photothermolysis: a pilot study. Dermatol Surg 2005;31:1645–50. 19. Kim BJ, Lee DH, Kim MN, et al. Fractional photothermolysis for the treatment of striae distensae in Asian skin. Am J Clin Dermatol 2008;9:33–7. 20. Rendon M, Berneburg M, Arellano I, et al. Treatment of melasma. J Am Acad Dermatol 2006;54:S272–81. 21. Briganti S, Camera E, Picardo M. Chemical and instrumental approaches to treat hyperpigmentation. Pigment Cell Res 2003;16:101–10. 22. Kang HY, Hwang JS, Lee JY, et al. The dermal stem cell factor and c-kit are overexpressed in melasma. Br J Dermatol 2006;154:1094–9. 23. Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol 2002;146:228–37. 24. Kim EH, Kim YC, Lee ES, et al. The vascular characteristics of melasma. J Dermatol Sci 2007;46:111–6. 25. Hantash BM, Bedi VP, Sudireddy V, et al. Laser-induced transepidermal elimination of dermal content by fractional photothermolysis. J Biomed Opt 2006;11:041115. 17. Tannous ZS, Astner S. Utilizing fractional resurfacing in the treatment of therapy-resistant melasma. J Cosmet Laser Ther 2005;7:39–43. 18. Kimbrough-Green CK, Griffiths CE, Finkel LJ, et al. Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial. Arch Dermatol 1994;130: 727–33. 1504 D E R M AT O L O G I C S U R G E RY Address correspondence and reprint requests to: Jin Ho Chung, MD, Department of Dermatology, Seoul National University Hospital, 28, Yongon-dong, Chongno-Gu, Seoul 110-744, Korea, or e-mail: [email protected]