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<p>From the Depa</p><p>Southwestern</p><p>tology, Plano</p><p>Cornell Medic</p><p>Dermatology,</p><p>of South Ca</p><p>Dermatology,</p><p>California, Da</p><p>California, Los</p><p>Medicine, Atla</p><p>Ford Hospital;</p><p>Detroit, Michig</p><p>School of Me</p><p>Pennsylvania.h</p><p>Best practices in the treatment of</p><p>melasma with a focus on patients with</p><p>skin of color</p><p>Seemal R. Desai, MD,a,b Andrew F. Alexis, MD, MPH,c Nada Elbuluk, MD,d Pearl E. Grimes, MD,e</p><p>Jonathan Weiss, MD,f Iltefat H. Hamzavi, MD,g and Susan C. Taylor, MDh</p><p>Background: Melasma is a chronic hypermelanosis of the skin that affects approximately 1% of the global</p><p>population, predominantly affects women, and is more prevalent in skin of color. Melasma is a common</p><p>driver for patients with skin of color to seek out a dermatologist for treatment, and ensuring the right</p><p>approach for these patients is important because some treatments may be associated with adverse side</p><p>effects. Because of the chronicity of the disease and established psychosocial and emotional impacts, there is</p><p>a large need to ensure care follows the best available evidence on the treatment of patients with melasma.</p><p>Objective: Here, we summarized current available topical treatments for melasma with considerations</p><p>dermatologists should have for their patients with skin of color.</p><p>Methods: Steering committee consensus on clinical best practices.</p><p>Results: We describe a flexible and focused treatment algorithm that reflects both treatment and</p><p>maintenance periods that is a consensus of our extensive clinical experience.</p><p>Limitations: Use of real-world evidence and potential for individual practice bias.</p><p>Conclusion: Melasma can be challenging to treat, particularly in patients with skin of color, and our</p><p>recommendations for best practices for patients in the United States are an important step toward</p><p>standardizing care. ( J Am Acad Dermatol 2024;90:269-79.)</p><p>Key words: cosmeceutical; fluocinolone acetonide; general dermatology; hydroquinone; maintenance</p><p>treatment; mechanical procedures; melasma; physical modalities; skin of color; tranexamic acid; treatment</p><p>algorithm; tretinoin.</p><p>INTRODUCTION</p><p>Melasma affects[5 million people in the United</p><p>States, with multiple global studies indicating that</p><p>melasma predominantly affects women and in pop-</p><p>ulations with skin of color (Fitzpatrick skin</p><p>rtment of Dermatology, University of Texas</p><p>Medical Center, Dallas, Texasa; Innovative Derma-</p><p>, Texasb; Department of Dermatology, Weill</p><p>ine, New York, New Yorkc; Department of</p><p>Keck School of Medicine Dermatology, University</p><p>lifornia, Los Angeles, Californiad; Division of</p><p>Vitiligo & Pigmentation Institute of Southern</p><p>vid Geffen School of Medicine, University of</p><p>Angeles, Californiae; Emory University School of</p><p>nta, Georgiaf; Department of Dermatology, Henry</p><p>Hamzavi Dermatology/Dermatology Specialists,</p><p>ang; and Department of Dermatology, Perelman</p><p>dicine, University of Pennsylvania, Philadelphia,</p><p>phototypes III-VI and non-White self-identified</p><p>racial/ethnic group).1-4</p><p>Melasma typically manifests as symmetric hyper-</p><p>pigmentation, primarily on sun-exposed areas, with</p><p>light brown to dark macules and patches on the face,</p><p>Funding sources: The development of this manuscript and pub-</p><p>lication costs were supported by Galderma Laboratories, L.P.</p><p>The sponsor had no role in the design, execution, interpreta-</p><p>tion, or writing of the manuscript.</p><p>IRB approval status: Not applicable.</p><p>Accepted for publication July 22, 2023.</p><p>Correspondence to: Seemal R. Desai, MD, Innovative Dermatology,</p><p>5655 W Spring Creek Pkwy, Suite 150, Plano, TX 75024. E-mail:</p><p>seemald@yahoo.com.</p><p>Published online September 23, 2023.</p><p>0190-9622</p><p>Published by Elsevier Inc. on behalf of the American Academy of</p><p>Dermatology, Inc.</p><p>https://doi.org/10.1016/j.jaad.2023.07.1045</p><p>269</p><p>http://crossmark.crossref.org/dialog/?doi=10.1016/j.jaad.2023.07.1045&domain=pdf</p><p>mailto:seemald@yahoo.com</p><p>https://doi.org/10.1016/j.jaad.2023.07.1045</p><p>J AM ACAD DERMATOL</p><p>FEBRUARY 2024</p><p>270 Desai et al</p><p>particularly on the forehead, cheeks, and chin in a</p><p>centrofacial pattern.1,5-9</p><p>The pathology behind melasma is complex.</p><p>Melasma represents a phenotype of photodamage</p><p>with epidermal and dermal changes, including an</p><p>increase in vascularity and mast cells.10 The multi-</p><p>faceted etiology of the disease is currently based on</p><p>CAPSULE SUMMARY</p><p>d There is a missing consensus on best</p><p>practices for use of prescription and</p><p>nonprescription therapies for patients</p><p>with melasma, particularly for those with</p><p>skin of color.</p><p>d A treatment algorithm is described as</p><p>identifying active and maintenance</p><p>therapies, to promote standardized care</p><p>for patients with melasma that is</p><p>inclusive for skin of color.</p><p>the intersection of the</p><p>following factors: UV radia-</p><p>tion exposure, visible-light</p><p>exposure, hormonal influ-</p><p>ences, and familial genetics.</p><p>UV radiation is a major driver</p><p>in melasma pathogenesis,</p><p>with data supporting its role</p><p>in sensitizing, triggering, and</p><p>aggravating the disease.11 UV</p><p>radiation is thought to stimu-</p><p>late melanogenesis by</p><p>increasing reactive oxygen</p><p>species production at the</p><p>cellular level and inducing</p><p>the synthesis of plasminogen</p><p>activator and plasmin activity in keratinocytes.12,13</p><p>UV radiation may increase certain hormones that</p><p>regulate melanogenesis and the severity of mel-</p><p>asma14 as aemelanocyte-stimulating hormone has</p><p>been found to be increased in melasma lesions.15</p><p>Studies have also shown that visible light can also</p><p>stimulate pigmentation.16,17 Both UV radiation and</p><p>visible light may stimulate cell signaling pathways,</p><p>including stem cell factor and vascular endothelial</p><p>growth factor.18-21 Heterogenous histologic findings</p><p>and various studies support that photoaging plays a</p><p>critical role in the development of melasma.10</p><p>REAL-WORD EVIDENCE</p><p>Because of its complex pathogenesis, melasma is</p><p>often recalcitrant to treatment, and recurrence is</p><p>common.10 A 2022 real-world evidence survey of US</p><p>dermatologists, physician assistants, and registered</p><p>nurses who treat patients in dermatology clinics</p><p>reported that melasma recurrence after treatment</p><p>discontinuation, along with the need for long-term</p><p>maintenance treatment, were the greatest challenges</p><p>that people with melasma experience.22 Patients</p><p>with melasma also struggle with adhering to their</p><p>treatment regimen, including the ongoing use of</p><p>broad-spectrum sunscreen and sun-protective</p><p>clothing (including hats).22 Many people with mel-</p><p>asma have tried different nonprescription treatments</p><p>and home remedies prior to seeing a dermatology</p><p>professional. This trial mindset, without professional</p><p>oversight, may further contribute to epidermal and</p><p>dermal changes and further confound the effective-</p><p>ness of prescription treatment.</p><p>The real-world evidence survey revealed that</p><p>dermatology specialists felt confident in diagnosing</p><p>melasma in all patients, including patientswith skin of</p><p>color, in educating their patients with skin of color</p><p>about melasma, and in their knowledge of melasma</p><p>management for any patient</p><p>phototype. Interestingly,</p><p>when asked about the top</p><p>educational needs to improve</p><p>their knowledge and confi-</p><p>dence in treating melasma in</p><p>patients with skin of color,</p><p>the top 3 needs were as</p><p>follows: (1) awareness of the</p><p>safety and efficacy of current</p><p>treatment options and how to</p><p>optimally prescribe; (2) up-</p><p>dated, more science-driven</p><p>guidelines or treatment algo-</p><p>rithms; and (3) knowledge on</p><p>how to combine nonpre-</p><p>scription and prescription products.22</p><p>Many dermatology practitioners are not adequately</p><p>trained to diagnose or treat skin conditions in people</p><p>of color.23 People with skin of color may present with</p><p>melasma differently and have different treatment</p><p>considerations, suggesting the need to update best</p><p>practices and offer guidance in treating melasma.</p><p>BEST PRACTICES FOR TREATMENT OF</p><p>MELASMA IN PATIENTS WITH SKIN OF</p><p>COLOR</p><p>With its complex pathogenesis, melasma is a</p><p>chronic disorder that dermatologic specialists can</p><p>treat and improve but not cure. Dermatologic</p><p>specialists and patients with melasma need to accept</p><p>that treatment and prevention is a long-term commit-</p><p>ment, combining photoprotection,</p><p>prescription ther-</p><p>apy, and nonprescription skin therapy to achieve the</p><p>best outcomes. During the initial consultation, it is</p><p>important to spend time educating patients on the</p><p>pathogenesis, complexities, and duration of treat-</p><p>ment, and the importance of adherence to treatment.</p><p>However, the real-world survey (Fig 1) revealed that</p><p>there is a lack of consensus on the role and order of</p><p>interventions for melasma, including use of photo-</p><p>protection, skin-lightening agents, and cosmeceuti-</p><p>cals.22 The lack of consensus supports the need for</p><p>evidence- and experience-based best practices and a</p><p>clinical treatment algorithm for the management of</p><p>melasma. Although there are a wide range of avail-</p><p>able melasma treatments,24,25 here we focus on</p><p>therapeutics that are commonly deployed in clinics.</p><p>Fig 1. 2022 Survey results ranking of the most common melasma treatment regimens. Survey</p><p>conducted on Medefield’s bespoke online survey system in English between September and</p><p>October 2022 in the United States. Questions primarily included predefined answer options</p><p>with completion of the survey implying informed consent. This research was considered ethics</p><p>review (institutional review board) exempt because it involved research in which persons</p><p>chose to anonymously complete an online survey.</p><p>J AM ACAD DERMATOL</p><p>VOLUME 90, NUMBER 2</p><p>Desai et al 271</p><p>Photoprotection/skin care</p><p>One of the challenges with treatingmelasma is the</p><p>lack of awareness or understanding among people,</p><p>especially those with skin of color, about the risks of</p><p>sun exposure and importance of sun protection.</p><p>Nonadherence to photoprotection is high, especially</p><p>in people with skin of color.26</p><p>Clinical data support that photoprotection,</p><p>specifically the regular use of a UV and visible-light</p><p>broad-spectrum sunscreen, is an important adjuvant</p><p>treatment in the prevention and treatment of mel-</p><p>asma. Using broad-spectrum sunscreens that filter or</p><p>block UV radiation and visible light in conjunction</p><p>with a topical treatment led to a greater decrease in</p><p>melanin content,27 whereas physically blocking or</p><p>filtering UV radiation has been shown to be an</p><p>effective method to reduce the severity of melasma</p><p>and limit flares.24,27-30</p><p>Patients with melasma should be counseled that</p><p>photoprotection, including a broad-brimmed hat and</p><p>sun avoidance, in conjunction with iron oxidee</p><p>containing sunscreen in any formulation is essential.</p><p>Tinted sunscreens, as well as sunscreens containing</p><p>antioxidants and free radical quenching, may also be</p><p>beneficial, especially in melasma-affected areas.</p><p>Diligent reapplication of sunscreen throughout the</p><p>day is an important consideration because melasma</p><p>can recur with minimal light exposure.</p><p>Skincare, including gentle cleansers and moistur-</p><p>izers, is an important setup for therapeutic</p><p>interventions because they to help restore skin</p><p>barrier function and increase skin moisture levels.</p><p>The real-world survey revealed that respondents</p><p>recommend skincare just over half as often as they</p><p>recommend photoprotection to patients with mel-</p><p>asma.22 Studies have shown that the skin barrier</p><p>function in melasma-affected skin is disrupted,</p><p>which may cause hyperpigmentation.31 Certain</p><p>treatments for melasma, especially physical proced-</p><p>ures (eg, chemical peels and laser treatments), may</p><p>further disrupt the skin barrier. Patients should be</p><p>counseled to use moisturizing products daily</p><p>because they may help improve tolerance and</p><p>reduce adverse reactions to therapeutic interven-</p><p>tions, increasing their regimen adherence.31</p><p>Skin-lightening agents</p><p>Melasma is a dysfunction of melanin production,</p><p>leading to an excessive accumulation of melanin in</p><p>the epidermis and dermis.14 Skin-lightening agents</p><p>(Table I), such as hydroquinone (HQ), may reduce</p><p>the production of melanin. The 2022 real-world</p><p>survey (Fig 1) revealed that HQ-containing creams</p><p>were the most common first-line treatments for</p><p>melasma. However, some respondents noted that</p><p>they had some safety concerns and a lack of certainty</p><p>about how to optimally prescribe HQ-containing</p><p>cream, including duration and cycling.22</p><p>This information is not surprising considering the</p><p>2022 US Food and Drug Administration (FDA)</p><p>Table I. Skin-lightening agents25,32-38</p><p>Therapeutic agent Mechanism of action Clinical data Side effects</p><p>FDA-approved fixed-</p><p>dose triple-</p><p>combination cream for</p><p>melasma</p><p>(4% HQ, 0.05%</p><p>tretinoin, and 0.01%</p><p>fluocinolone</p><p>acetonide)</p><p>HQdtyrosinase inhibitor; tretinoindstimulating</p><p>cell turnover and promoting epidermopoiesis;</p><p>fluocinolone acetonidedmay reduce irritation</p><p>and inflammation25,36</p><p>[5 randomized controlled trials</p><p>demonstrating efficacy and</p><p>safety; 1 long-term safety</p><p>([12 mo continuous use)25</p><p>Erythema, irritation, exogenous ochronosis</p><p>Compounded HQ No clinical studies found Erythema, irritation, exogenous ochronosis25</p><p>Azelaic acid Competitive tyrosinase inhibitor25 Small clinical trials showing</p><p>improvement in melasma25</p><p>Stinging, burning, itching, dryness25</p><p>Corticosteroids May reduce irritation and inflammation36 No clinical studies found Telangiectasias, epidermal atrophy, steroid-induced</p><p>acne, striae, hypopigmentation25</p><p>Retinoids Various pathway targets, which impact</p><p>melanin synthesis and dispersion, can</p><p>include inhibiting tyrosinase</p><p>transcription and melanin synthesis;</p><p>possible enhancement of transepidermal</p><p>penetration when combined topical</p><p>therapies25</p><p>No clinical studies found</p><p>for monotherapy25</p><p>Irritant reaction, dryness, hyperpigmentation25</p><p>Tranexamic acid Antifibrinolytic agent targeting melanocytee</p><p>keratinocyte interaction and angiogenesis25</p><p>Clinical studies demonstrating</p><p>reduction in melasma25</p><p>Oral: GI discomfort, allergic skin reactions, alopecia;</p><p>topical: erythema, scaling, dryness25</p><p>Heliocare (Polypodium</p><p>leucotomos)</p><p>Systemic photoprotective agent25 Small clinical trials showing</p><p>reduction in melasma25</p><p>Mild GI upset25</p><p>FDA, Food and Drug Administration; GI, gastrointestinal; HQ, hydroquinone.</p><p>J</p><p>A</p><p>M</p><p>A</p><p>C</p><p>A</p><p>D</p><p>D</p><p>E</p><p>R</p><p>M</p><p>A</p><p>T</p><p>O</p><p>L</p><p>F</p><p>E</p><p>B</p><p>R</p><p>U</p><p>A</p><p>R</p><p>Y</p><p>20</p><p>24</p><p>2</p><p>7</p><p>2</p><p>D</p><p>esa</p><p>i</p><p>et</p><p>a</p><p>l</p><p>J AM ACAD DERMATOL</p><p>VOLUME 90, NUMBER 2</p><p>Desai et al 273</p><p>warning letter issued to companies selling over-the-</p><p>counter skin-lightening products containing HQ that</p><p>were unapproved. The FDA had received reports of</p><p>serious side effects from these products, including</p><p>skin rashes, facial swelling, and ochronosis.39 Of</p><p>note, no adequate data exist supporting that HQ is</p><p>carcinogenic to humans.40 There have been no cases</p><p>in humans linking the topical use of HQ to any type</p><p>of cancer in[40 years of clinical use.40,41</p><p>The FDA warning letter noted that there are no</p><p>FDA-approved or otherwise legally marketed over-</p><p>the-counter skin-lightening products. Currently, there</p><p>is only one FDA-approved HQ-containing prescrip-</p><p>tion therapeutic (FDA-approved fixed-dose triple-</p><p>combination cream (TCC) for melasma; 4% HQ,</p><p>0.05% tretinoin, and 0.01% fluocinolone acetonide).39</p><p>TCC</p><p>The FDA-approved fixed-dose TCC for melasma</p><p>(4% HQ, 0.05% tretinoin, and 0.01% fluocinolone</p><p>acetonide) is considered a first-line treatment for</p><p>melasma with proven safety and efficacy.32 It is</p><p>approved for the short-term treatment (up to</p><p>8 weeks) of dark spots associated with moderate-</p><p>to-severe melasma of the face. The triple combina-</p><p>tion of agents inhibits the production of melanin</p><p>(HQ), promotes the rapid loss of pigment through</p><p>increased epidermal turnover (tretinoin), and in-</p><p>hibits the synthesis of melanin mediators (fluocino-</p><p>lone; topical steroid). The topical steroid may also</p><p>play a role in reducing potential irritation from the</p><p>other ingredients.42</p><p>There are studies demonstrating the effectiveness</p><p>of HQ, retinoids, and corticosteroids in treating</p><p>melasma as monotherapies43-48; however, the FDA-</p><p>approved fixed-dose TCC for melasma is more</p><p>efficacious than the individual monotherapies and</p><p>dual-therapy combinations.25,32-35 One long-term</p><p>study (n = 173) reported that once-daily application</p><p>of the FDA-approved therapy over an extended</p><p>12-month period showed no notable safety con-</p><p>cerns, with 90% of study participants being either</p><p>completely, or nearly,</p><p>clear by the end of the study.</p><p>Overall, 2.5% of patients discontinued the study</p><p>because of adverse events.36 Other clinical data</p><p>support the safety of the FDA-approved fixed-dose</p><p>TCC for up to 24 weeks when used intermittently or</p><p>continuously.37</p><p>The real-world survey revealed that compounded</p><p>topical products are also being used to treat mel-</p><p>asma.22 The FDA describes compounding as</p><p>combining, admixing, mixing, diluting, pooling,</p><p>reconstituting, or otherwise altering of a drug or</p><p>bulk drug substance to create a drug product.49 TCC</p><p>can be compounded in private clinics or certain</p><p>pharmacies, with one advantage typically being</p><p>lower cost to the patient and removing concerns</p><p>over the copay.50 Most therapeutics compounded by</p><p>dermatologists are considered to be at low risk for</p><p>safety issues because they are usually for topical use</p><p>or intradermal injection51; however, there can be</p><p>safety risks in compounding therapeutics.50,52,53</p><p>Concentrations of HQ [4% are being created in</p><p>compounding pharmacies with some compounding</p><p>6%, 8%, 10%, and higher HQ formulations. There are</p><p>limited safety or efficacy data on HQ used in</p><p>concentrations [4% and our, the authors, clinical</p><p>experience cautions going [12% HQ. The poor</p><p>physicochemical stability of HQ and its hydrophilic</p><p>nature, which impacts its permeability, is a com-</p><p>pounding challenge. Penetration enhancers and</p><p>other agents are needed to optimize the transdermal</p><p>delivery of HQ, leading to variability in the physico-</p><p>chemical characteristics of different formulations,</p><p>ultimately impacting its stability, efficacy, and</p><p>toxicity.54</p><p>Other topical prescription therapies</p><p>Other topical prescription therapies are also being</p><p>used to treat melasma as monotherapies or as</p><p>compounded products. HQ, corticosteroids, reti-</p><p>noids, and azelaic acid are the most used active</p><p>ingredients in compounded therapies. These prod-</p><p>ucts are often used as part of the rotation of treatment</p><p>with HQ-containing TCCs because the monotherapy</p><p>agents may cause less irritation. Corticosteroids are</p><p>often combined with other agents to minimize their</p><p>impact and the risk of epidermal atrophy, telangiec-</p><p>tasias, and rosacea-like erythema.41 When used as</p><p>monotherapies, the components have reportedly</p><p>caused adverse events, such as irritant dermatitis</p><p>and, with long-term use, exogenous ochronosis,</p><p>telangiectasias, acne, epidermal atrophy, striae, and</p><p>hypopigmentation (Tables I and II).47,55</p><p>Oral therapies</p><p>Topical therapies are the preferred treatment</p><p>option for melasma. Oral medications may be an</p><p>option as part of triple-combination therapy rotation</p><p>or in patients who have experienced adverse re-</p><p>actions to topical agents. Tranexamic acid (TA) is a</p><p>plasmin inhibitor leading to a decrease in</p><p>melanogenic factors, such as prostaglandins and</p><p>aemelanocyte-stimulating hormone, decreasing</p><p>melanin synthesis.57 TA also appears to reduce</p><p>erythema in melasma skin through its reduction of</p><p>endothelial growth factor and mast cells, leading to a</p><p>reduction in melanin synthesis.13,57 Note that TA is</p><p>not FDA-approved for the treatment of melasma.</p><p>Table II. Cosmeceutical treatment of melasma38,42,56</p><p>Agent Mechanism of action Clinical data Side effects</p><p>Azelaic acid Antioxidant; free radical</p><p>scavenger, tyrosinase</p><p>inhibitor38,42,56</p><p>Small clinical trials showing</p><p>improvement in melasma38,42,56</p><p>Stinging, burning, itching, dryness38</p><p>Botanical-based therapies (eg,</p><p>arbutin)</p><p>Decreases melanogenesis; inhibits</p><p>melanocyte maturation56</p><p>Small clinical trials showing</p><p>improvement in hyperpigmentation38,56</p><p>Skin irritation38</p><p>Cysteamine Antioxidant; free radical scavenger38 Multiple clinical trials showing improvement</p><p>in melasma38</p><p>None reported</p><p>Ferulic acid Antioxidant properties56 Small clinical trials showing improvement</p><p>in melasma56</p><p>None reported</p><p>Kojic acid Decreases melanogenesis;</p><p>antioxidant properties56</p><p>Small clinical trials demonstrating some</p><p>improvement in melasma38,42,56</p><p>Contact dermatitis, irritation, erythema,</p><p>redness, stinging38,42</p><p>Licorice root Anti-inflammatory; decreases</p><p>melanogenesis38,42,56</p><p>Multiple clinical trials demonstrating</p><p>improvement in melasma38,56</p><p>None reported</p><p>Niacinamide Antioxidant, inhibits</p><p>melanosome transfer38,56</p><p>Small clinical trials showing improvement in</p><p>hyperpigmentation56</p><p>Burning, erythema, pruritus, irritation38,56</p><p>Resorcinol Decreases melanogenesis56 Small clinical trials showing improvement in</p><p>hyperpigmentation and melasma56</p><p>Mild stinging, burning, pruritus, erythema56</p><p>Retinol Inhibits oxidative stress; inhibits</p><p>melanosome transfer; regulates</p><p>keratinocyte differentiation and</p><p>increases exfoliation56</p><p>Small clinical trials showing improvement in</p><p>hyperpigmentation38,56</p><p>Erythema, scaling, and hyperpigmentation38,56</p><p>Thiamidol Decreases melanogenesis56 Small clinical trials showing improvement in</p><p>hyperpigmentation56</p><p>No adverse events reported56</p><p>Vitamin C Decreases melanogenesis;</p><p>antioxidant properties42,56</p><p>Multiple clinical trials demonstrating decrease in</p><p>melasma and increase in QoL38,42,56</p><p>Stinging, burning, erythema, pruritus,</p><p>irritation, scaling56</p><p>J</p><p>A</p><p>M</p><p>A</p><p>C</p><p>A</p><p>D</p><p>D</p><p>E</p><p>R</p><p>M</p><p>A</p><p>T</p><p>O</p><p>L</p><p>F</p><p>E</p><p>B</p><p>R</p><p>U</p><p>A</p><p>R</p><p>Y</p><p>20</p><p>24</p><p>2</p><p>7</p><p>4</p><p>D</p><p>esa</p><p>i</p><p>et</p><p>a</p><p>l</p><p>Table III. Procedural, mechanical, and energy-based procedures</p><p>Procedural</p><p>d Superficial chemical peels</p><p>d Microneedling</p><p>d Intralesional tranexamic acid</p><p>d Intralesional platelet-rich plasma</p><p>Use with caution; recommended for those with experience in</p><p>treating darker skin tones</p><p>Energy-based</p><p>d Intense pulse light (lighter skin tones, types 1-3)</p><p>d Radiofrequency microneedling</p><p>Use with caution; recommended for those with experience in</p><p>treating darker skin tones</p><p>Lasers</p><p>d Nonablative fractional laser</p><p>d Low-fluence Q-switched Nd:YAG laser</p><p>d Pulse dye laser</p><p>d Picosecond laser</p><p>Use with caution; recommended for those with experience in</p><p>treating darker skin tones</p><p>J AM ACAD DERMATOL</p><p>VOLUME 90, NUMBER 2</p><p>Desai et al 275</p><p>Studies indicate that TA is an effective treatment</p><p>in melasma patients, including those who do not</p><p>respond to common topical therapies, and appears</p><p>to be a good agent to treat vascular melasma.25,57-61</p><p>Oral TA has been used with TCC, with data</p><p>suggesting that the oral/topical combination in-</p><p>creases efficacy.62,63 Data support that oral TA is</p><p>the most effective delivery method, followed by</p><p>intradermal injection and topical as an adjuvant</p><p>therapy with laser.13,60 Studies support that TA, in</p><p>patients without risk factors, does not increase</p><p>thromboembolic risk; however, patients should be</p><p>screened carefully for contraindications and risk</p><p>factors prior to use.64</p><p>Another unapproved oral therapy is the natural</p><p>product Polypodium leucotomos extract, commer-</p><p>cially available as Heliocare, which acts as a</p><p>photoprotection agent.65 There is conflicting evi-</p><p>dence on its overall efficacy in treating melasma,</p><p>with some studies demonstrating moderate bene-</p><p>fits.66-68</p><p>Melatonin and pycnogenol are unapproved</p><p>agents that have shown some benefit, in combina-</p><p>tion with topical HQ, in decreasing melasma, with</p><p>limited data on the efficacy and safety of these</p><p>compounds.38,69</p><p>Cosmeceuticals</p><p>Vitamin C, kojic acid, niacinamide, and azelaic</p><p>acid (Table II) are all natural compounds that target</p><p>hyperactive melanocytes and decrease melanogen-</p><p>esis, leading to an improvement of melasma symp-</p><p>toms when used as topical compounds.12,45,70-73</p><p>None of the described cosmeceutical monotherapies</p><p>have reported improved efficacy over HQ-</p><p>containing TCC.46,48,74</p><p>Physical, mechanical, and energy-based</p><p>procedures</p><p>Mechanical procedures, physical modalities, or</p><p>energy-based procedures can be helpful adjuvants to</p><p>treat melasma, facilitating epidermal remodeling,</p><p>epidermal and dermal melanin elimination, and</p><p>dermal reorganization. Caution should be exercised</p><p>when using mechanical, physical, or energy-based</p><p>procedures, particularly in darker skin tones because</p><p>some procedures have limited clinical data and carry</p><p>risks of rebound melasma and hyperpigmentation.75</p><p>Adjunctive procedures (Table III) should be used</p><p>appropriately in patients with melasma and conser-</p><p>vatively in patients</p><p>with skin of color.</p><p>SUMMARY</p><p>Melasma is a chronic, relapsing skin disorder that</p><p>requires lifelong care. Currently, there is no cure.</p><p>Treatment can be challenging, especially in the</p><p>moderately to severely affected patient with the</p><p>need for treatment rotationdactive treatment cycled</p><p>with maintenance therapy. Dermatology specialists</p><p>need to understand the pathology of the disorder,</p><p>including factors, such as higher UV exposure in</p><p>certain seasons, patient occupation, and lifestyle.</p><p>Counseling on melasma and the importance of</p><p>photoprotection, such as daily sun protection, is the</p><p>first step in the management of melasma.</p><p>Tolerability of topical agents and adherence</p><p>should be considered in decisions regarding pre-</p><p>scription products. Patients need simple regimens to</p><p>follow, no more than 2 to 3 steps, with clear</p><p>directions on how and when to use each product.</p><p>Skin-lightening agents combined with photopro-</p><p>tection have potential to reduce the appearance of</p><p>hyperpigmented areas of melasma. FDA-approved</p><p>fixed-dose TCC for melasma remains a foundation of</p><p>Fig 2. Melasma treatment algorithm.</p><p>J AM ACAD DERMATOL</p><p>FEBRUARY 2024</p><p>276 Desai et al</p><p>care with robust safety and efficacy data. Our</p><p>recommendation is to prescribe HQ-containing</p><p>TCC for 2 to 6 months and then to cycle patients</p><p>onto maintenance therapy with other topical or oral</p><p>therapies and noneHQ-containing cosmeceuticals</p><p>for 3 to 6 months before cycling back onto the HQ-</p><p>containing TCC (Fig 2). Physical and energy-based</p><p>procedures may be cautiously considered as an</p><p>adjunct to skin-lightening agents. Treating melasma</p><p>requires a multimodal approach with physical, me-</p><p>chanical, and energy-based procedures being an</p><p>important part of the therapeutic armamentarium,</p><p>and topical therapies as an integral part of the</p><p>treatment regimen. Another manuscript on best</p><p>J AM ACAD DERMATOL</p><p>VOLUME 90, NUMBER 2</p><p>Desai et al 277</p><p>practices using nontopical modalities to treat mel-</p><p>asma would be an asset to the dermatologic</p><p>community.</p><p>Maintenance therapy and treatment tapering</p><p>remain an ongoing challenge for patients with</p><p>melasma, with higher incidences of relapse in</p><p>patients who have transitioned treatment.37,76</p><p>Cycling back to prescription HQ-containing therapy</p><p>or adjunct therapies in response to relapse may be</p><p>necessary. Cosmeceuticals may be best used as an</p><p>adjunct to HQ-based combination therapy or used as</p><p>part of the maintenance regimen.</p><p>Careful consideration is required as we determine</p><p>the optimal treatment regimen for our patients with</p><p>melasma, particularly those patients with skin of</p><p>color. Limited safety and efficacy data exist, espe-</p><p>cially with long-term use, for TA and many topical</p><p>treatments for melasma, including cosmeceuticals</p><p>and compounded HQ and noneHQ-containing</p><p>products.50,77 Dermatology specialists need to bal-</p><p>ance reducing melanogenesis and restoring the</p><p>epidermis and dermis with the simplest treatment</p><p>regimen.</p><p>The authors acknowledge writing and editorial support</p><p>by Bonnie Kuehl, PhD, and Christopher Go, PhD, in the</p><p>development of the manuscript.</p><p>Conflicts of interest</p><p>Dr Desai has served as a consultant and/or investigator</p><p>for Galderma, Pfizer, Dermavant, Scientis, AbbVie, and</p><p>several other organizations. He also serves in multiple</p><p>leadership roles with dermatologic organizations. Dr</p><p>Alexis has received grants from LEO Pharma, Novartis,</p><p>Almirall, Bristol Myers Squibb, Amgen, Vyne, Galderma,</p><p>Valeant (now Bausch Health), Cara, Arcutis, Dermavant,</p><p>AbbVie, and Castle and consulting fees or honoraria from</p><p>Leo, Galderma, Pfizer, Sanofi-Regeneron, Dermavant,</p><p>Beiersdorf, Ortho, L’Oreal, Bristol Myers Squibb, Bausch</p><p>Health, UCB, Vyne, Arcutis, Janssen, Allergan, Almirall,</p><p>AbbVie, Sol-Gel, Amgen, VisualDx, Eli Lilly, Swiss</p><p>American, Cutera, Cara, EPI, and Incyte. He has also</p><p>received speaker fees from Regeneron, Sanofi-Genzyme,</p><p>Pfizer, and Bristol Myers Squibb. Dr Elbuluk has received</p><p>fees, research funding, or stock options for consulting,</p><p>speaking, or participating in advisory boards from</p><p>Allergan, Avita Medical, Beiersdorf, Est�ee Lauder,</p><p>Galderma Laboratories, Incyte, Janssen, La Roche-Posay,</p><p>L’Oreal, Scientis, Unilever, and VisualDx. Dr Grimes has</p><p>served as a consultant and/or investigator for Procter &</p><p>Gamble, Clinuvel, L’Oreal, Galderma Laboratories,</p><p>LaserOptek, Versicolor Technologies, Incyte, Pfizer,</p><p>AbbVie/Allergan, and SkinBetterScience. Dr Weiss served</p><p>on the advisory board for Galderma Laboratories and</p><p>Valeant Pharmaceuticals International (now Bausch</p><p>Health), receiving honoraria. He also served as consultant</p><p>for Abbott Laboratories, Celgene Corporation, LEO</p><p>Pharma, and Sebacia, receiving honoraria. Dr Hamzavi is</p><p>a consultant to AbbVie, Pfizer, Incyte, UCB, Boerhinger</p><p>Ingelheim, Sonoma, Union therapeutics, Novartis, Janssen,</p><p>Avita, and for Galderma Laboratories. Dr Hamzavi is an</p><p>investigator for LENICURA, Pfizer, Incyte, Avita, and</p><p>L’Oreal/La Roche-Posay. He is a board member and past</p><p>president of the HS Foundation and Global Vitiligo</p><p>Foundation. Dr Taylor reports service as an investigator</p><p>for Concert Pharmaceuticals, Croma-Pharma, Eli Lilly,</p><p>and Pfizer. Dr Taylor has received salaries, fees, honoraria,</p><p>and stock options as a consultant, advisor, board member,</p><p>and speaker for Mercer Strategies, AbbVie, Arcutis</p><p>Biotherapeutics, Armis Scientific, Beiersdorf, Biorez, Cara</p><p>Therapeutics, EPI Pharma, Evolus, Galderma Laboratories,</p><p>Glo Getter, Hugel America, Janssen, Johnson &</p><p>JohnsonJohnson & Johnson, L’Oreal, Medscape/WebMD,</p><p>MJH Life Sciences, Piction Health, Regeneron, Scientis US,</p><p>UCB, and Vichy Laboratoires.</p><p>REFERENCES</p><p>1. Handel AC, Miot LDB, Miot HA. Melasma: a clinical and</p><p>epidemiological review. An Bras Dermatol. 2014;89(5):771-</p><p>782. https://doi.org/10.1590/abd1806-4841.20143063</p><p>2. Sangha AM. Dermatological conditions in SKIN OF COLOR-</p><p>melasma: topical and systemic management. 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