Treatment of Unwanted Pigment

Transcription

1 16 Treatment of Unwanted Pigment Elizabeth W. Chance, MD 1 1 Department of Plastic Surgery, Martha Jefferson Hospital, Charlottesville, Virginia Facial Plast Surg 2014;30: Address for correspondence Elizabeth W. Chance, MD, Department of Plastic Surgery, Martha Jefferson Hospital, 600 Peter Jefferson Parkway, Suite 270, Charlottesville, Virginia ( ewchance@sestera.com). Abstract Keywords solar lentigines melasma postinflammatory hyperpigmentation Disorders of skin pigmentation pose significant challenges to both patients and physicians, as they have the unfortunate duality of being both common and difficult to treat conditions. This article reviews the etiology, pathophysiology, clinical presentation, and treatment options for melasma and postinflammatory hyperpigmentation. A thorough understanding of the disease process itself, expected agent efficacy, risks, and benefits of various treatments is crucial while treating these complex conditions. Disorders of skin pigmentation pose significant challenges to both patients and physicians, as they have the unfortunate duality of being both common and difficult to treat conditions. On a cellular level, hyperpigmentation of the skin occurs as the result of local derangement of melanin production and melanocytes. Several distinct clinical entities exist under the large umbrella term of hyperpigmentation. This article will review the epidemiology, pathophysiology, clinical presentation, and treatment options for the most common types of dyspigmentation: solar lentigines, melasma, and postinflammatory hyperpigmentation (PIH). A thorough understanding of these differing disease processes, expected agent efficacy, risks, and benefits of various treatments is crucial while treating these complex conditions. Epidemiology Solar lentigines are the most common form of dyspigmentation. Lentigines present as well- circumscribed, homogeneously pigmented macules located on areas of chronically sun-exposed skin, such as the arms, trunk, neck, and face. These lesions are traditionally the first sign of skin photoaging and can begin to develop as early as the fourth decade of life. Fair skin individuals are predominantly affected, with studies reporting lentigines present in nearly 90% of Caucasians older than 50 years with men and women affected at similar rates. 1 Unlike melasma and PIH, darker phototype skin appears to be less affected by this form of dyspigmentation. 2 Melasma is a psychologically distressing, chronic disorder of skin hyperpigmentation primarily occurring in women, affecting millions worldwide and approximately 5 million within the United States. 3 Patients with darker skin types including those of African, Asian, Latino, and Middle Eastern descent show a greater tendency toward developing melasma, with Fitzpatrick phototypes III IV most commonly affected. 4 Various studies have shown incidences ranging from 8% in the Latino population to prevelances as high as 40% in Southeast Asia. 5 Surveys indicate melasma has a strong genetic component, evidenced by high incidences amongst family members. 6 8 Geography also impacts the prevalence of melasma, with patients living in elevated ultraviolet (UV)- exposure regions at increased risk for development. PIH is an acquired increase in pigmentation occurring secondary to cutaneous injury or inflammatory response. PIH can arise in all skin types, but similar to melasma, more commonly affects patients with the darker Fitzpatrick skin types III VI. There is a paucity of data on the exact incidence of PIH, however, epidemiologic studies show that dyspigmentation due to PIH is among the most common reasons for darker racial/ethnic groups to seek the care of a dermatologist. Unlike melasma, which shows a predilection toward women, women and men are equally affected and PIH can be seen at any age. 9 Histopathology of Hyperpigmentation Deregulation of melanocytes and increased production of melanin are the pathophysiologic link between solar lentigines, melasma, and PIH. To understand these disease processes, one must first understand the cellular mechanism by which the phenotype of dyspigmentation occurs. Melanocytes are Issue Theme Classical and State-of-the- Art Skin Rejuvenation; Guest Editors, Lisa D. Grunebaum, MD, and Noëlle S. Sherber, MD, FAAD Copyright 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) DOI /s ISSN

2 Treatment of Unwanted Pigment Chance 17 pigment-producing cells located within the basal layer of the epidermis, where these cells generate a specialized organelle called the melanosome. Within melanosomes, melanin or pigment granules are synthesized which give skin its specific color. Dendritic arms of melanocytes branch widely from this basal layer to contact adjacent and more superficial keratinocytes within the skin s epithelium, allowing for transfer of the melanosomes to these cells. Variations in size and aggregations of melanosomes give rise to skin color variations between races. In dark skin, large melanosomes are singly dispersed to keratinocytes and slower degradation of the increased epidermal melanin is noted. 10 The higher rate of melasma and PIH and other pigmentary disorders in skin-of-color patients is the direct result of larger melanosomes within melanocytes, higher melanin-production levels, and increased melanin concentration leading to an exaggerated response of these prevalent cells to cutaneous injury. 11 Visible and UV light play a pathologic role in the development of all three conditions of lentigines, melasma, and PIH. Histologically, solar lentigines demonstrate increased melanin within basal melanocytes and elongated dermal papilla, both attributed to the effects of UV radiation induced cellular damage. 12 Cellular exposure to light radiation has been shown to upregulate the biologic activity of melanocytes in melasma-affected skin, with ensuing overproduction and overaccumulation of both free and phagocytized melanin within the skin s layers. Documented melasma improvement during the winter, impact solely on sun-exposed skin, and histologic evidence of solar elastosis, erythema, and increased tissue vascularity in the macules of melasma supports the role of visible and UV light radiation in the pathogenesis of melasma While PIH is initiated by a cutaneous injury, PIH can worsen with UV irradiation due to UV-induced melanocyte stimulation. 16 In addition to external factors such as sun exposure, development of melasma is also linked to internal factors such as hormone fluctuation due to pregnancy or oral contraceptives, thyroid disorders, and exogenous medications. Clinical studies have identified pregnancy and oral contraceptive use as inciting events for development of melasma in a significant percentage of women, while several tissue studies have noted estradiol s ability to increase melanin synthesis in culture and a possible stimulatory effect of estrogen and progesterone on melanocytes. 17,18 The primary driving cellular mechanism behind PIH is the overproduction of melanin or aberrant dispersion of pigment following cutaneous inflammation. 11 The inflammatory response is believe to upregulate melanocyte activity through the actions of cytokines, chemokines, prostaglandins, and other inflammatory cells, although the exact mechanism is poorly understood. Within the epidermis, this inflammatory cascade drives increased production and transfer of melanin to adjacent keratinocytes. Injury within the dermis results in release of melanin from damaged basal melanocytes, which is then phagocytized by macrophages/melanophages. The engulfed melanin within the upper dermis produces a blue-gray discoloration to the skin, which is distinct from the lighter brown dyspigmentation secondary to melanin excess within the epidermis. 19,20 Clinically, as discussed in a later section, treatment of the excess pigment in patients with PIH cannot begin before the inciting inflammatory trigger is treated. Clinical Features Also known as age spots, liver spots, or sun spots, solar lentigines are the most common benign disorder of skin hyperpigmentation. Commonly affected areas are classically sun-exposed regions, including the face, arms, dorsa of the hands, and upper part of the trunk. A solar lentigo (plural: lentigines) is typically round or oval and can range in size from millimeters to several centimeters, with multiple lesions often coalescing into larger patches. Lentiginous macules are classically flat, often uniformly pigmented light to dark brown lesions, but may range in color from yellow-brown to black. Borders of the spots often have irregular or moth eaten appearance. Clinicians should be able to distinguish solar lentigines from pigmented lesions such as ephelides, seborrheic keratosis, melanocytic nevus, lentigo maligna melanoma, and malignant melanoma based on appearance. Characteristics such as color variegation or pigmentation appearing red, blue, or dark brown pigmentation should raise clinician suspicion for malignancy and result in tissue biopsy. Melasma, derived from the Greek word melas meaning black, presents as symmetrical hypermelanotic macules that occur most commonly on the face or extensor surface of the forearms 21 ( Fig. 1). Melasma can be referred to by the term chloasma, or the mask pregnancy, given its proclivity to arise during the hormonal fluctuations of pregnancy. Skin affected by melasma appears light brown to dark brown or tan, but pigmentation can vary from these typical colors to gray, blue, or black. Three distinct facial patterns have Fig. 1 Melasma of the cheek, temple, forehead, and upper lip, showing inhomogeneous pigmentation.

3 18 Treatment of Unwanted Pigment Chance traditionally been identified for melasma: centrofacial, malar, and mandibular. Centrofacial melasma is the most common form and is characterized by macules on the cheeks, forehead, upper lip, and/or chin. Malar melasma is limited to the malar and cheek region and occurs in 20to 50% of patients. 13,22 Mandibular melasma pattern is the least common and occurs primarily on the mandible or is limited to the mandibular ramus. 22 Melasma is further subclassified into epidermal, dermal, mixed epidermal dermal, or indeterminate type based on the location of the aberrant pigmentation within the skin s layers. The Wood lamp has historically been used for diagnosis and subclassification of melasma; UV light will fluoresce melanin within the epidermis, whereas no enhancement of pigmentation located in the dermis will occur. Indeterminate subtype describes deeply pigmented (FP type VI) skin where the Wood lamp evaluation cannot determine a fluorescence pattern secondary due to the high density of normal melanocytes within the darker skin. 13 Recent studies have cast doubt on the Wood lamp ability to accurately predict epidermal versus dermal pigment deposition. 13,23,24 Grimes et al 24 recently reported on 13 patients classified as having epidermal melasma by Wood lamp exam whose tissues showed deposition of melanin throughout the dermis. As dermal melasma has historically been more resistant to treatment than its more superficial counterpart, the presence of dermal melanin in patients thought to have epidermal melasma based on Wood lamp evaluation may shed light on why some superficial melasma is refractory to treatment with topical medications PIH can be considered the default pathophysiologic response to cutaneous injury in darker skin phototypes. Clinically, PIH-affected skin demonstrates macules or patches in the same distribution as the initial inflammatory insult. In PIH-prone individuals, any insult causing skin erythema has the potential to incite hyperpigmentation. Like melasma, excess pigment is deposited in epidermis or both epidermis and dermis and color of the pigmented patch will vary based on depth of melanin (superficial, tan/brown; dermal, blue/ gray). Also in line with melasma, epidermal PIH is more likely to improve with time and medical treatment, whereas dermal hyperpigmentation is typically more refractory to treatment. Inflammatory processes that trigger PIH include acne vulgaris, atopic dermatitis, impetigo, pseudofolliculitis barbae, trauma, burns, psoriasis, cutaneous drug eruptions, lichen planus, and allergic contact dermatitis, among others. 29 Of these conditions, acne vulgaris is likely the most common PIH-inducing trigger, with a recent study of more than 1,400 dermatologic visits at a major metropolitan clinic identifying 65.3% of African American (N ¼ 239), 52.7% of Hispanic (N ¼ 55), and 47.4% of Asian (N ¼ 19) patients as developing acne-induced PIH. 30 Wood lamp has also been used to classify PIH as epidermal, dermal, or mixed subclassification types. PIH has been shown to worsen with persistent or recurrent inflammation or with prolonged exposure to UV light. 9 Before instituting any therapy for PIH, the underlying inflammatory dermatosis must first be addressed. Medical Therapy Prevention Photoprotection is the most critical, mainstay therapy for treatment of these conditions, as continued exposure to UV radiation drives the underlying mechanisms of melanocyte activation. Use of daily sunscreen year round, regardless of sun exposure, has been found to dramatically reduce the incidence of melasma development. 31,32 Recommended sunscreen includes both UVA and UVB (broad spectrum) coverage, at least sun protective factor (SPF) 30 that is formulated with physical blocking agents such as zinc oxide or titanium dioxide. 33 Physical blocking sunscreens are recommended as they will reflect both UVA and UVB rays, rather than absorbing them, and also are less likely to irritate acne-prone skin. For the many patients of darker pigmentation who have not required mineral sunscreens to block visible light during their lifetime, the importance of sunscreen to avoid the darkening effects of UV radiation must be emphasized and a habit formed. Sunscreen should be reapplied throughout the day on a regular basis. Sun avoidance is also recommended, as heat also may play a role in hyperpigmentation pathogenesis. Topical Treatments Hydroquinone In addition to sunscreen, a mainstay of dyspigmentation treatment is topical hydroquinone (HQ). HQ is a skin bleaching agent that works by blocking production of melanin through inhibition of tyrosinase, which converts dihydroxyphenylalanine to melanin. HQ may also reduce pigment by stimulating melanosome degradation, destruction of melanocytes, and by altering melanocyte production at the deoxyriboneucleic acid (DNA) and riboneucleic level. Over-thecounter preparations of HQ are available at 2% in the United States, whereas 4% is the commonly prescribed strength for both melasma and PIH treatment. Higher treatments strengths are rarely used but are available by prescription, with 10% HQ saved for severe pigmentary disorders. HQ is applied twice daily to the areas of pigmentation for an average of 3 to 6 months, depending on patient s response. 34 Adverse effects include allergic contact dermatitis, nail discoloration, postinflammatory pigmentation, hypopigmentation of surrounding skin, or rarely onchronosis. 35 For high phototype skin (Fitzpatrick IV VI) at risk for adverse side effects, patients should be monitored routinely every 3 months of use. Patients with lighter skin types should be monitored every 6 months. 34 Recently, controversy has arisen over the safety profile of HQ. A rare but significant risk of HQ use is development of exogenous ochronosis (EO), a blue-gray pigmentation of the skin seen most commonly in blacks of South Africa who were treated with high dose HQ over long periods of time. 36 In EO, homogentisic acid accumulates in the skin causing sun exposed areas treated with HQ to develop hyperpigmentation and papules. In 2001, the European Union banned HQ in overthe-counter preparations over concern of side effects such as

4 Treatment of Unwanted Pigment Chance 19 ochronosis and vitiligo. 37 The United States Food and Drug Administration (FDA) released a statement in 2006 proposing a ban on all over-the-counter HQ products based on murine studies indicating carcinogenic potential for oral HQ administration. Outcry against the proposed FDA HQ ban by the dermatologic community in the United States was significant. Long-term studies of use of topical HQ over a 50-year period were publically cited, showing no link between topical HQ use and carcinoma development and an extremely low risk of EO amongst American HQ users. 38,39 Data comparing plasma/ blood levels of HQ after topical application compared with blood levels following to dietary intake of arbutin, a natural substance found in coffee, whole wheat, and pear skin which hydrolyzes to yield free HQ, showed blood levels to be equivalent between the two. As arbutin-containing foods, such as coffee, are not believed to be carcinogenic, topical HQ likely retains a similar safety profile based on its low bioavaibility. 39,40 The FDA ruling on the proposed 2006 legislation is currently pending. Mequinol Mequinol, 4-hydroxyanisole, is a skin lightening agent with a similar mechanism of action of HQ that is frequently used in treatment of dyschromias. Mequinol is available by prescription as a single agent (2% concentration) or as a combination cream, typically compounded with a low-concentration retinoid. Multiple large-population studies have demonstrated mequinol s effectiveness in treating solar lentigines in all patients including darkly pigmented populations A consensus statement by the Pigmentary Disorders Academy (2006) reported that use of a fixed double combination therapy of hydroxyanisole mequinol and retinoid was considered standard initial medical therapy for solar lentigines. 45 Several small studies indicate successful use for PIH and melasma Retinoids Retinoids used as topical monotherapy have been shown beneficial in treating hyperpigmentation. Retinoids are functional analogs of vitamin A and are thought to be effective in treating hyperpigmentation by inhibiting tyrosinase enzyme production, interfering with melanin synthesis, and stimulating cell proliferation and turnover. 49,50 Two specific forms of topical retinoids, tretinoin (all-trans-retinoid acid) and adapalene (a naphthoic acid derivative with retinoid activity) have shown promise in treating hyperpigmentation when used as monotherapy. 51,52 Tretinoin is prescribed in 0.05 and 0.1% strengths in treating hyperpigmentation, however treatment is often limited by mild-to-moderate cutaneous adverse effects of erythema, pruritus, burning, and desquamation. A randomized control trial comparing 0.1% adapalene versus 0.05% tretinoin in 30 Indian patients over a 14-week course found a 41% reduction in Melasma Area and Severity Indiex (MASI) score in the adapalene group versus 37% reduction in the tretinoin-treated group. Patients in the adapalene group reported less side effects and greater tolerance to the medication when compared with the tretinoin. 52 Adapalene has also be proven efficacious in lightening solar lentigines, with a study of both 0.1 and 0.3% adapalene gel showing lightening of lentiginous lesions by 57 and 59%, respectively. Studies assessing tretinoin and adapalene monotherapy in treating PIH have also shown promising results. 53,54 If retinoid use is chosen as monotherapy in treated hyperpigmentation, compliance can be increased by counseling patients on appropriate dosing recommendations such as utilizing a pea-sized amount of the face every 2 to 3 nights, and gradually increasing to nightly use as the skin becomes tolerant. Retinoid-induced erythema must be avoided, as this can induce PIH. Retinoid therapy alone may not be sufficient for more severe forms of hyperpigmentation. Combination Products Treatment of hyperpigmentation may require a combination of topical treatments to treat stubborn or recalcitrant disease. Dual therapy with combined HQ and tretinoin (RA þ HQ) has shown success in treating hyperpigmentation when compared with HQ alone Cook-Bolden and Hamilton 56 conducted a trial of twice daily treatment with microencapsulated 4% HQ and retinol 0.15% with antioxidants in 21 patients with PIH (n ¼ 17) and melasma (n ¼ 4), the majority of which had FP type IV VI skin. Reported results showed significant reduction in hyperpigmentation as early as week 4 and extending through the 12-week study period. One limitation of daily use of 4% or higher HQ concentrations when combined with retinoids has been irritant reactions, which can further drive the PIH process. 57,58 Caution must be used in these patients when instituting combined therapy with these specific products. More recent studies 47 have tested the efficacy of RA þ HQ therapies against triple combination creams (TCC) formulated with HQ, tretinoin, steroid, and found a statistically significant improvement with the addition of the fluorinated steroid in hyperpigmentation treatment. A multicenter, randomized, investigator-blinded study comparing the efficacy and safety of a cream formulation containing tretinoin 0.05%, HQ 4.0%, and FA 0.01% (RA þ HQ þ FA) with the dual-combination RA þ HQ, tretinoin plus FA (RA þ FA), and HQ plus FA (HQ þ FA) showed a very statistically significant improvement with the use of the triple cream combination therapy. Results showed 26.1% of patients treated with TCC experienced complete clearing of pigmentation over an 8-week time period, compared with dual therapy treatment groups (4.6%) (p < ). In addition, a 75% reduction in melasma/pigmentation was observed in more than 70% of patients treated with TCC compared with 30% in patients who were treated with the dual combination creams. 59 The tested TCC in this study, Triluma (Galderma, Fort Worth, TX), is currently FDA approved for treatment of melasma. Similar randomized, blinded control trials have shown comparable findings when comparing HQ alone versus triple therapy. 60,61 Caution must be exercised when prescribing TCC, as topical use of steroid therapy should be monitored for development of known side effects including steroid acne and telangiectasia development. Over concern for the steroid-induced dermal atrophy, treatment recommendations are for use of this TCC once to twice daily for 2 to 3 months followed by reduction to

5 20 Treatment of Unwanted Pigment Chance an HQ/retinol regimen. If no recurrence of hyperpigmentation has occurred 1 year following institution of the regimen, therapy should be reduced to nightly topical retinoid use. 62 It must be stressed to patients that continued, faithful SPF use alongside these daily therapies is the optimal therapy for hyperpigmentation. More formal studies are still needed to study TCC use in PIH. Azelaic Acid Azelaic acid is a topical treatment produced naturally by the yeast Pityrosporum ovale that has been shown to be effective in the treatment of acne, rosacea, and skin hyperpigmentation. Its skin-lightening effects appear to be due to competitive inhibition of tyrosinase and interruption of mitochondrial activity and DNA synthesis in abnormal melanocytes. 63 Azelaic acid cream is available in concentrations of 15 to 20%, with 20% cream reserved for treatment of melasma and PIH. Multiple studies have shown topical azelaic acid monotherapy to be equally or more effective in treating hyperpigmentation than HQ alone Azelaic acid s niche in the treatment of hyperpigmentation may be twofold: use in patients who cannot tolerate HQ therapy and treatment of pregnant and breastfeeding patients for pregnancy-induced dyspigmentation, as it is safe in these conditions. Kojic Acid Kojic acid (KA) is a naturally occurring tyrosinase inhibitor found as a fungal metabolic product of various Aspergillus and Penicillium species. 67 KA cream is available over the counter in 1 to 4% preparations, but can be combined with glycolic acid (GA) and HQ in prescription form to increase efficacy of the product. Lim 68 reported greater melasma improvement with the addition of KA in a split-face trial of 2% KA þ 10% GA þ 2% HQ cream versus 10% GA þ 2% HQ. A split-face 3- month trial of GA 5% combined with either 4% KA or 4% HQ demonstrated roughly equivalent results between agent combinations, although increased skin irritation was noted in the KA-treated group. 69 Several additional studies have identified KA as an irritant and responsible for contact dermatitis, which must be kept in mind given its inclusion in many over-the-counter multiagent preparations Additional Topical Treatments A host of other agents including ascorbic acid, soy, arbutin, ellagic acid, rucinol, niacinamide, N-acetyl glucosamine, and licorice root have various mechanisms for targeting melanogenesis and have been utilized in the treatment of hyperpigmentation. Although many of these compounds have not shown great promise as single-agent treatments, many may have some role in adjunctive therapy against both melasma and hyperpigmentation. Procedures Procedures utilized in the treatment of hyperpigmentation include cryotherapy, superficial and medium-depth chemical peels, intense pulsed light (IPL), and laser therapy. These therapies are typically utilized as an adjuvant to topical treatments, with the exception of cryotherapy which can be used as a first line treatment for solar lentigines. Caution must be exercised when performing any of these procedural treatments darker complexion patients, given their tendency for PIH. Prevention and management of PIH after the application of various agents including chemical peels are of great importance while treating melasma in darker skin phototypes. Throughout use of any adjuvant treatment, maintenance of daily SPF use is critical. Cryotherapy Topical application of cyrogens, including carbon dioxide, nitrous oxide, and commonly used liquid nitrogen, represent the most common and perhaps the most efficacious method for treatment of solar lentigines. Cryotherapy works by freezing the temperature-sensitive melanocytes, which are destroyed by temperatures of 4 to 7 C. Single application treatments are often found effective in eliminating solar lentigines. 73 Several studies have shown significant improvements in lesion appearance and degree of pigmentation with single-treatment cryotherapy. 74,75 In a study of 30 patients with smaller solar lentigines treated to 32 C using cryotherapy, Almond-Roesler noted 80% improvement in patients treated for 5 seconds and 100% improvement with treatment increased to 10 seconds. The authors noted mild skin atrophy in 10 and 60% of patients, respectively. A similar study compared use of liquid nitrogen cryotherapy on solitary large solar lentigines and found full remission of all lesions in their six patients treated, with no recurrence noted at 10-month follow-up. 74 Although these two studies have relatively low enrollment, studies comparing cryotherapy with laser therapy, dermabrasion, chemical peels, and other treatments demonstrate the effectiveness of cryotherapy in treatment these types of pigmented lesions. 75 Alpha Hydroxy Acid Peels GA is a naturally occurring alpha hydroxy acid (AHA) found in sugarcane. Topical application of GA reduces pigmentation by accelerating cell turnover, dispersing melanocytes with the skin s basal layer, and decreasing barrier function of the skin allowing for improved distribution of topical therapies GA s use in the treatment of dyspigmentation is bolstered by its lack of significant complications with use on darker skin phototypes. 79 Burns et al 80 demonstrated improvement in PIH in patients with Fitzpatrick skin types IV VI treated with six GA peels (50 68% concentration) over a 3-week period. Compared with the control group treated utilizing 2% HQ/10% GA gel twice daily and nightly 0.05% tretinoin cream, the peel group trended toward more rapid and greater improvement in PIH. Combination 70% glycolic and 40% trichloroacetic acid (TCA) peels showed success in treating solar lentigines both on nonfacial skin. Sarkar et al 79 reported the use of serial GA peels of 30 to 40% concentration at 3-week interval in patients treated concomitantly with TCC (Kligman formula) compared with TCC alone. The authors noted faster resolution of

6 Treatment of Unwanted Pigment Chance 21 hyperpigmentation compared with topical TCC alone at 21- week treatment; however, end-treatment differences in efficacy were noted. Pretreatment with HQ or tretinoin before GA peel may be of added benefit. 81 Lactic Acid Peels Lactic acid (LA) is also an AHA with similar chemical properties to GA. Recent study of 92% LA peel use in 30 patients found a significant fall in MASI (56%) for the 12 patients who completed the study, with results maintained at 6 months. 82 The same group compared treatment with LA versus Jessner s peels for hyperpigmentation and reported equal efficacy between the two treatments. 83 Greater research is needed for LA peels to become more common choice in the treatment of hyperpigmentation. Salicylic Acid Peels Salicylic acid (SA) is a β-hydroxy acid used to treat of both melasma and PIH resulting from acne. Like GA, SA disrupts the barrier function of keratinocytes allowing for removal of pigmented epithelial cells and deeper absorption of topical therapies. Treatments are typically in concentrations of 20 to 30% and do not require neutralization. 84 Grimes 85 reported improvement in skin hyperpigmentation and acne in patients with darker phototype skin using a protocol of repeated SA peels and topical 4% HQ use. The safety of repeat SA peel use in FP type IV VI skin has been repeated documented. 84,86,87 Because of SA s comedolytic and anti-inflammatory properties, it is a useful tool in patients with PIH from acne vulgaris. 86 Other Available Peels TCA and Jessner s solution peels are also used as treatments for hyperpigmentation due to melasma. Efficacy of both peel types has been found to be on par with GA or LA treatments in treating melasma. 83,88 Safety of these agents in treating PIH in FP type IV VI skin has not been established. Laser and Light Therapies The use of lasers and light therapy in the treatment of skin hyperpigmentation should be considered as second or thirdline therapy for treatment of dyspigmentation and performed by trained, experienced physicians. Laser therapy principle must be comprehensively understood before treating pigmented skin, as incorrect parameters can result in exacerbation of hyperpigmentation particularly in darker skin phototypes. Regardless of laser regimen, preoperative preparation of the skin should involve strict sun avoidance, topical skin lightening agents before and after treatment, pretreatment photography, informed consent, and appropriate counseling of patients on reasonable expected outcomes. Understanding the dynamics and parameters for targeting melanin with laser light is critical in treating patients. Cutaneous lasers have three primary target chromophores in the skin, water, melanin, and hemoglobin. Melanin has a broad absorption band within the UV, visible, and infrared light spectrums (250 and 1,200 nm), whereas oxyhemoglobin has three absorption peaks in at 415, 542, and 577 nm. Targeting melanin requires laser wavelengths longer than 600 nm to avoid absorption by oxyhemaglobin and resulting vascular damage. 89 Melanin more efficiency absorbs energy at short wavelengths, however longer wavelengths are required to penetrate deeper into dermal skin, allowing for targeting of dermal melanin. Wavelengths shorter than 600 nm also damage melanin at lower energy density (fluence), whereas longer wavelengths (> 600 nm) require greater fluences to damage melanosomes. Intense Pulsed Light (Lasers) Intense pulsed light (IPL) has shown promise in treating dyspigmentation in FP type I V skin. IPL is high intensity, incoherent, and multichromatic light that emits light spectrum in the range of 500 to 1,200 nm in millisecond pulse durations. IPL treatments are most useful in treating superficial (epidermal) hyperpigmentation, as short pulse durations preclude treatment of dermal melanosomes, which have nanosecond-range thermal relaxation times. 90 A recent randomized control trial by Wang et al 91 treated Asian patients with refractory melasma either with IPL and HQ versus HQ alone. IPL parameters were within 570 to 615 nm filters to target melanin with low fluences and long pulse delays. The IPL treatment group was noted to have a significant treatment response (39.8% improvement in relative melanin index in four sessions at 4-week intervals) when compared with the control group (11.6% improvement) (p < 0.05). Of 17 patients, 2 patients were noted to experience PIH and partial return of hyperpigmentation at 24 weeks following the final treatment session, concluding that further sessions are required for maintenance therapy. Various additional studies have shown the efficacy of IPL in treating epidermal pigmentation Caution should be used when treating dyscromias with IPL at higher fluences, as inducing PIH when treating darker skin phototypes becomes a significant risk. Nonablative Lasers Quality switched lasers, including Q-switched Nd:YAG, Q- switched Ruby, and Q-switched Alexandrite lasers have been studied in the management of pigmentary disorders, however few studies have shown treatment benefits, leading most authors to not recommend these therapies in treatment of several types of hyperpigmentation. 34,90,94 96 Treatment failures in these early Q-switched laser studies have been attributed to use of high-fluence, single pass treatments utilized, that would exacerbate pigmentation and cause temporary or permanent hypopigmentation. A recent study 97 on the effect of low fluence QS Nd:YAG combined with microdermabrasion and topical HQ has shown some promise in treatment of refractory melasma in phototype II V skin

7 22 Treatment of Unwanted Pigment Chance without the increased levels of relapse seen in previous study. Patients were treated with low-fluence QS Nd:YAG laser treatment of 1.6 to 2 J/cm 2 with 5- or 6-mm spot administered immediately following microdermabrasion, performed at 4-week intervals. Broad-spectrum sunscreen and topical skin care regimen of HQ with tretinoin or vitamin C were used throughout the study period. Of the patients enrolled, 22 (81%) patients had > 75% clearance of melasma, with 11 subjects (40%) achieved > 95% clearance. Success of the treatment was attributed to a combination of low-fluence laser settings as well as continued use of topical SPF and HQ therapy. Q-switched ruby and Nd:YAG lasers have individually shown promise in the treatment of solar lentigines. In a study by Kopera et al, 98 histologic evaluation of lentigines treated with Q-switched ruby laser (single pulse/single treatment) showed phototheramal damage and evaporation of target pigment within the epidermis and dermis. Evaluation of 91 solar lentigines in patients with darker phototype skin (II IV) treated with Q-switched ruby laser light demonstrated complete resolution of all lesions in all patients at 6 months, as judged by a blinded dermatologist s treatment. All improved over a 6-month period, demonstrating promising results with this treatment modality. 99 Postinflammatory dyspigmentation was noted to have developed in 7.8% patients with Fitzpatrick skin type II, 9.8% patients with type III, and 16.6% patients with type IV (p ¼ 0.67). Further study on low-fluence Q-switched or convention nonablative lasers is ongoing in the treatment of hyperpigmentation. Fractional Photothermolysis Fractionated photothermolysis (FP) has been touted as the laser treatment of choice for hyperpigmentation, however recent studies have shown mixed successes. The nonablative erbium-doped 1,550-nm laser treats excess pigmentation by creating full thickness columns of tissue injury, and allowing for clearance of the pigment through tissue destruction and repopulation of the zones of injury with normal cells and melanocytes. Also, by creating these smaller columns, or microzones, of thermal injury, rapid recovery with less downtime is seen. 100 Increased use of the 1,550 nm erbium laser in treating melasma following enthusiasm based on a pilot study by Rokhshar et al, 101 which reported high melasma clearance rates following repeated laser applications. A total of 10 females ranging from FP type III V with recalcitrant melasma were treated in four to six treatment sessions, with results showing 60% of patients with 75 to 100% clearing of melasma according to physician assessment. Patient assessment of their own improvement found that 50% rated themselves as having 75 to 100% improvement. Subsequent studies also demonstrated moderate success with fractional in the treatment for melasma. 102,103 Split-face randomized control trial of FP versus TCC in 29 patients with melasma demonstrated an unacceptably high rate of hyperpigmentation with fractional laser treatments after four to five nonablative 1,550 nm laser treatments. 104 The 31% rate of development of PIH was attributed to the higher energy microbeam used in this study compared with others (10 mj). A similar study published 1 year later by the same research group involving 10-mJ microbeam settings with the 1,550 nm laser found similar rates of improvement in comparing 1,550 nm fractional therapy compared with TCC in the treatment of 20 female patients with melasma. 105 Another recent study demonstrated no statistically significant difference between subjective and objective improvement in 26 melasma patient treated with four sessions of 1,550 nm fractional laser with daily sunscreen versus 25 melasma patient controls treated with daily sunscreen alone. 106 Despite its FDA approval status for the treatment of melasma, use of the 1,550 nm erbium laser on this refractory condition has shown mixed shortterm and long-term results. The 1,927 nm non-ablative thulium fiber laser (Fraxel re: store DUAL, Solta Medical, Hayward, CA) has shown potential for effectiveness in the treatment of dyspigmentation. The higher absorption coefficient for water of the 1,927 nm thulium when compared with the 1,550 nm erbium laser allows for more superficial penetration and improved targeting of epidermal processes, such as certain dyscromias. A pilot study by Polder et al 107 in 2011 assessed 14 patients FP II IV treated with three to four sessions of the 1,927 nm laser at varied parameters (10 to 20 mj, 20 45%, six to eight passes) and found a statistically significant drop of 51% in the MASI score 1 month following treatment. Follow-up assessment at 3 and 6 months demonstrated a 33 and 34% reduction in MASI from baseline, respectively. Observers did not report scarring or postinflammatory hyper or hypopigmentation with this treatment. A study of 20 women FP II IV with melasma were who underwent a single, high-density treatment with the 1,927 nm fractionated thulium laser (settings: 10 or 20 mj/cm 2 with 60 70% coverage, 3 days postlaser treated with corticosteroid cream) demonstrated a mean MASI score decrease from to at 4 weeks following treatment (p ¼ 0.004). 108 Of 20 patients, 12 patients at greater than 50% clearance of their melasma when assessed by independent raters. However, recurrence was noted in 7 of 15 patients at 10.2-month follow-up, which resolved following 3 months of utilizing topical bleaching creams. Low-density treatment with the 1,927 nm laser was investigated in a split-face study of 25 Asian women with skin photoaging (eight with melasma) who underwent three consecutive laser treatments with 10 mj, 30% density spaced at 3 week intervals. 109 Independent evaluators noted 33% reduction in MASI score at 2 months and 28% at 6 months. Both aforementioned trials reported significant levels of rebound, however neither study utilized bleaching agents during the trial period. Further investigation of combined therapy with the 1,927 nm fractionated laser and topical bleaching treatments may be the next frontier of treatment for this stubborn condition. Summary Solar lentigines, melasma, and PIH are common, persistent skin conditions seen worldwide touching all races and skin

8 Treatment of Unwanted Pigment Chance 23 types. The recalcitrant nature of hyperpigmentation dictates that multiple approaches to treatment including topical therapies, chemical peels, and laser or light therapy. Before instituting therapy, it is important to set expectations as significant time and effort may be requirement for treatments to be successful. Medical therapy with topical agents including bleaching creams, retinoids, and topical steroids should be instituted first, followed by escalation to chemical peels and laser therapy should the first-line not result in resolution. When treating darker phototypes, care must be taken to avoid treatment induced hyperpigmentation which may preclude aggressive regimens. Practitioners must understand the emotion, psychologic and social impact of these disease processes when treatment patients with pigment disorders. Emphasizing the importance of sun protection and sun avoidance to patients suffering with hyperpigmentation is paramount. 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