Melasma and Post Inflammatory Hyperpigmentation: Management Update and Expert Opinion

Bryan Sofen, MD¹; Giselle Prado, BS²; Jason Emer, MD³

¹Rush University Medical Center, Chicago, Il, USA
²Florida International University, Herbert Wertheim College of Medicine, Miami, FL, USA
³Spalding Drive Plastic Surgery and Cosmetic Dermatology, Beverly Hills, CA, USA

Conflict of interest: None Reported.

ABSTRACT
Dyschromia is a leading cause for cosmetic consultation, especially in those with diverse skin types (mixture of ethnicities) and with the rise of non-core and untrained physicians performing cosmetic procedures. Melasma and post-inflammatory hyperpigmentation (PIH) account for the majority of cases and are characterized by pigmented macules and patches distributed symmetrically in sun-exposed areas of the forehead, cheeks, and chin in melasma, and irregularly in areas of inflammation or an inciting traumatic event with PIH. Treatment is challenging and focused on a variety of mechanisms to stop, hinder, and/or prevent steps in the pigment production (melanocytic hyperactivity) process, breaking down deposited pigment for internal removal or external release, exfoliating cells to enhance turnover, and decreasing inflammation. Topical lightening therapy in combination with sun protection is essential for potential improvement. The most commonly prescribed and researched topical lightening agents are hydroquinone (HQ), azelaic acid (AzA), and retinoids – although only HQ and a triple combination cream (Tri-Luma®; fluocinolone acetonide 0.01%, HQ 4%, tretinoin 0.05%) are US FDA-approved for “bleaching of hyperpigmented skin” (HQ) and “melasma” (Tri-Luma®). Numerous non-HQ brightening/lightening agents, including antioxidant and botanical cosmeceuticals, have recently flooded the market with improvements that claim less irritant potential, as well as avoiding the stigmata associated with HQ agents such as carcinogenesis and cutaneous ochronosis. Combining topical therapy with procedures such as chemical peels, intense pulsed light (IPL), fractional non-ablative lasers or radiofrequency, pigment lasers (microsecond, picosecond, Q-switched), and microneedling, enhances results. With proper treatment, melasma can be controlled, improved, and maintained; alternatively, PIH can be cured in most cases. Herein, we review treatments for both conditions and provide an opinion on proper management for enhanced results.

Key Words:
melasma, post-inflammatory hyperpigmentation, dyschromia, hydroquinone, azelaic acid, Q-switched lasers, picosecond lasers, microneedling, management, chemical peels, fractional laser, skin bleaching

Introduction

Dyschromia is a frequent complaint in the cosmetic consultation as it is psychologically distressing and may be a signal of systemic changes (e.g., hormones, sun sensitivity/autoimmune, medications).¹ Although dyschromia is more commonly reported in those with darker or diverse skin types, there is an increasing number of patients of all skin types seen in practice presenting with irregular macules and patches of hyper and hypopigmentation from improperly performed cosmetic procedures by non-core or untrained physicians inducing color changes (Figures 1a and 1b). Given the degree of importance patients place on a clear complexion with regards to color and tone, we set forth to describe updated treatment options for melasma and post-inflammatory hyperpigmentation (PIH) to guide proper management.

Melasma is an acquired disorder of pigmentation that is characterized by symmetrically distributed pigmented macules and patches in sun-exposed areas of the face such as the forehead, cheeks and chin. Although the pathogenesis is not completely understood, hyperactive melanocytes stimulated by ultraviolet (UV) light exposure is the most widely accepted cause. UV exposure stimulates an increase in tyrosinemediated melanogenesis and melanosome transfer to epidermal keratinocytes, which is reflective of what we see clinically with worsening of pigmented patches after sun exposure or burn. Other causes such as genetics, photosensitizing medications, and hormones/endocrinopathies also play a role and may contribute to UV sensitivity.² Estrogen, associated with pregnancy or oral contraceptive pills, induces the release of melanocyte-stimulating hormone (MSH), stimulating tyrosinase; a reason the majority of cases are seen in females versus males.³

In lesional skin of patients with melasma, there is upregulation of vascular endothelial growth factor (VEGF), stem cell factor (kit-ligand), Wnt (Wingless-related integration site) signaling modulating genes, and reactive oxygen species, all of which are byproducts of UV induced dermal inflammation that in turn promote vascularization and stimulate melanocyte hyperactivity.⁴ This local inflammatory milieu is also seen in PIH.³

PIH represents another form of reactive hypermelanosis that occurs following an inciting event, which causes cutaneous inflammation such as inflammatory skin conditions (e.g., psoriasis, eczema, acne), trauma (e.g., picking, burns), or cosmetic procedures (Figure 2).⁵ The majority of cases are irregularly placed and not symmetrical or necessarily in sunexposed areas, as seen in melasma. Patients with darker or diverse skin types are more prone to PIH due to higher basal amounts of epidermal melanin. PIH is gender neutral, conversely, melasma is much more common in females due to hormonal influences.⁵ Histologically, there is no difference between either entity and clinical correlation is essential. Epidermal and dermal pigmentation may be differentiated on biopsy or with Wood’s lamp examination to dictate the nature of treatments offered at the onset.

Treatment of disorders of pigmentation can be challenging. For PIH, the key component guiding all other treatment remains prevention. PIH may be prevented or minimized by using pre-procedural topical lightening/bleaching agents, antiinflammatories, and/or retinoids. In contrast, melasma prevention is quite difficult. Patients with a family history of melasma or a diverse or ethnic skin type, who are pregnant, on hormonal therapy, or taking a photosensitizing medication, should be counseled on appropriate skin care with photoprotection, antioxidants, and lightening agents. While PIH may resolve spontaneously without treatment, melasma has no cure and needs continuous topical therapy focused on protection from UV damage in addition to targeted lightening/bleaching. This paper will review the common topical and procedural treatments for melasma and PIH.

Discussion

The treatment of melasma is frustrating due to its relapsing nature, few therapies offering a cure, and a struggle for successful preventative options. Alternatively, PIH can be prevented and often clears spontaneously on its own despite therapies that are available. Photoprotection and topical medical treatments are critical to the management of both entities in order to suppress melanogenesis (Table 1). In addition, medical treatments (both topical and procedural) work to aid in the removal of excess melanin that is already deposited.

Photoprotection

Photoprotection underscores all treatment modalities for disorders of pigmentation, particularly melasma. Without photoprotection, minimal benefit will be seen with any other therapeutic option. UVB (290-315 nm), UVA (315-400 nm), and even visible light (400-700 nm) all stimulate melanocytes to produce melanin and in some instances can overproduce observable pigmentation.⁶ While the lower wavelength UVB has the highest energy of this group and is the most erythemogenic, both UVA and visible light have a greater impact on stimulating melanogenesis and creating more chronic pigmentation.⁷ Broadspectrum sun protection against both UVA and UVB is critical, with physical blockers such as those with zinc or titanium dioxide the most recommended; however, sunscreens with the addition of chemical photosensitizers such as avobenzone (Parsol® 1789), octocrylene (Milestab™ 3039), oxybenzone (Helioplex®), and ecamsule (Mexoryl™) can increase the spectrum of protection by decreasing the production of free radicals while remaining photostable and absorbative. Many broad-spectrum sunscreens do not fully protect against the visible light spectrum that may contribute to pigmentary exacerbation; this is why compounds such as Tinosorb® M (not available in the United States) are added. Tinosorb® M increases the stability of other UV filters (like octinoxate, Eusolex®/Uvinul®) and has an inherent ability to reflect and scatter most wavelengths (with the majority being UVA and UVB). Additional benefit has been seen in sunscreens tinted with compounds such as iron oxide that also protect against visible light.⁸ Sun-protective clothing and broad rimmed hats are also key components to a comprehensive photoprotection strategy. Additionally, Polypodium leucotomos (fern extract, Heliocare®) is an oral antioxidant that has shown photoprotective effects and is recommended by the authors for all patients with pigmentary concerns or those undergoing any laser therapy.^9-10

Topical Therapies

Hydroquinone and Combination Therapy

The best-studied and most widely used topical depigmenting agent is hydroquinone (HQ), a structural analog of melanin precursors that inhibits the conversion of L-3,4-dihydroxyphenylalanine (L-DOPA) to melanin by tyrosinase. Adverse cutaneous effects include irritation, allergic contact dermatitis, and rarely ochronosis. Multiple studies have shown that the depigmenting effect is augmented when combined with a retinoid and a corticosteroid.^3,11-13 A triple combination cream of HQ 4%, fluocinolone acetonide 0.01%, and tretinoin 0.05%(Tri-Luma®) is the most widely used, although many compounded variants are used in clinical practice today. To prevent long-term sequela such as ochronosis from HQ products, it is suggested that practitioners limit treatment to 3-6 months continuously and then take a HQ “holiday.”¹⁴ However, shortterm continuous therapy with long-term “weekend only” or “3 times weekly” maintenance therapy has substantial benefit for treating both melasma and PIH with very few complications. Concerns over cutaneous carcinogenesis have not been confirmed in clinical practice and are not a concern to these authors when topical HQ products are used as described above (Figure 3).

Retinoids interfere with melanosome transfer to keratinocytes, accelerate pigment loss by increasing epidermal turnover, and directly inhibit tyrosinase.¹⁵ The use of retinoids as monotherapy is not recommended as an irritant reaction may cause inflammation that induces paradoxical hyperpigmentation; a similar concern exists over the use of HQ as monotherapy at very high concentrations (i.e., 8-20%). The addition of a low potency topical corticosteroid (see Tri-Luma® above) helps limit irritation, improves epidermal penetration, and prevents oxidation of HQ, thereby giving a synergistic improvement over HQ alone.¹⁶

A 2010 open-label study of 70 patients with moderate to severe melasma showed that 67.7% of patients achieved results of “clear” or “mild” disease as evaluated by the study researchers after 12 weeks of daily treatment with triple therapy.¹² Another study of 242 patients showed twice weekly maintenance treatment kept 53% of patients symptom free for 6 months.¹⁷

Non-Hydroquinone Alternatives

A number of HQ alternative (tyrosinase inhibition) products have flooded the market due to a demand for ingredients with less irritation and less stigma (i.e., ochronosis and carcinogenesis) than HQ. AzA, tranexamic acid, resorcinol, mequinol, and kojic acid are common constituents, often as part of a combination of agents used for lightening.18-22 AzA has intrinsic antityrosinase activity, but also acts as an anti-inflammatory agent.¹⁵ Tranexamic acid is a plasmin and prostaglandin inhibitor that leads to reduced tyrosinase activity.²³ Kojic acid, a naturally derived fungal metabolite, is a potent antioxidant and has been used in combination therapy with good success given its ability to enhance epidermal penetration of other medications through improved cell turnover.

Botanicals and Cosmeceuticals

Botanically derived antioxidants and natural extracts are frequently used for skin lightening due to their skin brightening and anti-inflammatory effects (Table 2). Silymarin, arbutin, resveratrol, Aloe vera, pycnogenol, Boswellia, aloesin, niacinamide, ascorbic acid, and extracts of coffeeberry, soy, green tea, orchids, grape seed, marine algae, and licorice are some of the more common agents seen in cosmeceutical products.^3,24 Arbutin, a derivative of hydroquinone derived from plants, inhibits melanosome maturation and tyrosinase activity and is one of the most widely used skin-lightening agents worldwide.¹⁶ Niacinamide (vitamin B3) interferes with the interaction between keratinocytes and melanocytes by modulating the proteaseactivated receptor (PAR-2) that is involved in melanosome transfer.²⁵ Ascorbic acid is a natural antioxidant that interacts with copper ions in the tyrosinase active site and acts as a reducing agent in various steps of melanogenesis to inhibit pigment formation.¹⁶ Coffeeberry is another antioxidant whose effects of depigmentation have not yet been adequately studied but has been found to be helpful as an alternative treatment of melasma.¹⁶ Soy’s skin lightening effects are mediated by PAR-2 and DOPA oxidase inhibition.

SkinCeuticals® Advanced Pigment Corrector, composed of a proprietary combination of a synthetic tyrosinase inhibitor (hydroxyphenoxy propionic acid), a flavonoid antioxidant (0.5% ellagic acid), 5% yeast extract, and 0.3% salicylic acid, showed similar results in terms of skin tone, spot intensity, spot size, and hyperpigmentation in a 12 week study compared to combination 4% HQ and 0.025% tretinoin cream.²⁶ The SkinCeuticals® formulation had significantly less adverse effects such as irritability.

SkinMedica® Lytera® Skin Brightening Complex is a combination of tetrahexyldecyl ascorbate (vitamin C), niacinamide (vitamin B3), ethyl linoleate (essential fatty acid) and squalene (lipid), retinol, Dunaliella salina extract (carotenoids of phytoene and phytofluene extracted from unicellular algae), hexylresorcinol, tetrapeptide-30 (skin brightening peptide), 4-ethoxybenzaldehyde, and Glycyrrhiza glabra (licorice) root extract (rich in glabridin, an antioxidant). This unique proprietary combination of ingredients work together to brighten and even skin tone and texture, improve luminosity, and reduce the appearance of dark spots through inhibition of tyrosinase, increasing keratinocyte turnover, improving the natural skin barrier (lipid), and decreasing inflammation (antioxidants). A split face study of 68 Caucasian women with moderate to severe facial hyperpigmentation with different dose formulations of Lytera® Skin Brightening Complex versus 4% hydroquinone showed the highest patient satisfaction with Lytera® and the lowest with 4% hydroquinone. All subjects achieved a significant reduction in overall hyperpigmentation.²⁷

Elure® Advanced Skin Brightening Technology has a natural enzyme formulation Melanozyme® that is mushroom-derived (ligninase) and a natural inhibitor of tyrosinase. In a randomized, double-blind, placebo-controlled, split-face, single-center study of 51 patients, twice daily application of this enzyme on one-half of the face led to a mean 7.6% improvement in pigmentation as measured by Mexameter® (to asses melanin and erythema values) after 31 days. The other half of the face was randomized to receive either 2% hydroquinone or placebo and did not result in a statistically significant lightening effect.²⁸

Melaplex® is a patented combination of disodium glycerophosphate, L-leucine, phenylethyl resorcinol, and undecylenoyl phenylalanine. Both the biosynthesis of melanin (tyrosinase inhibition) as well as the transfer of melanosomes to keratinocytes is inhibited (by decreasing the supply of L-tyrosine).^29-30

Chemical Peels

Chemical peels are frequently reported in the literature as effective for the treatment of hyperpigmentation such as melasma.^3,31 Superficial peels such as salicylic acid, Jessner’s solution (salicylic acid and lactic acid with resorcinol) and glycolic acid are reported to provide improvement with the least risk of complications. Stronger peeling agents such as multiple pass Jessners, Jessner’s/trichloroacetic acid (TCA) combination, TCA 35% or phenol, induce much more inflammation and the potential to significantly worsen pigmentation. It is the author’s preference (JE) to limit chemical peeling agents for the treatment of hyperpigmentation with the exception of salicylic acid (or lowdose combination peels, see below) due to the intrinsic ability for this agent to decrease inflammation, which is a reason it functions well as a peeling agent in other skin conditions like rosacea.

More recently, combination peeling agents such as the Vi Peel® (TCA, retinoic acid, salicylic acid, phenol, and vitamin C) group of peels, have the ability to address a range of skin complaints such as pigmentation, scarring, wrinkles, pores and acne in all skin types due to the low-strength combination of multiple agents that work while inducing little inflammation. The Vi Peel® with Precision Plus is a booster peel with the ingredients listed above plus the addition of HQ, kojic acid, and hydrocortisone, yielding improved treatment of melasma and PIH.

Intense Pulsed Light

Intense pulsed light (IPL) is not considered a first-line treatment for melasma or PIH.¹ Initial studies for the treatment of melasma showed improvement compared to control, but results were rarely sustained and, in some instances, showed the condition worsening.³² Results were improved if topical triple therapy was combined with IPL treatments, as compared with triple therapy alone.^33-34 Although there are some studies documenting improvement in PIH with IPL, it is not a standard therapy as one of the more common complications from IPL treatment, even when well performed, is post-inflammatory dyschromia.³⁵ Moreover, IPL is not ideal for Fitzpatrick skin types 4 to 6, comprising the more common population of patients with melasma and PIH. IPL for pigmentation should be considered as a last resort therapy employing very conservative treatment parameters, and administered through a series of sessions combined with an appropriate lightening skin care regimen and sun protection.

Lasers

Although lasers are reported in many studies to be helpful for the treatment of melasma (and in some instances PIH), in reality, there is a significant limitation to laser-based devices for pigmentation given the risk of rebound pigmentation or worsening, even with conservative treatment.^3,11 Theoretically, selective photothermolysis of melanosomes should induce destruction of excessive pigmentation, but any irritation or inflammation has the ability to induce reactive melanocytosis and, thus, worsen pigmentation.³⁶ In addition, post-procedural photosensitivity (along with hormonal induced photosensitivity seen in melasma) poses a major problem for long-term maintenance of results without an intensive brightening, anti-inflammatory, and sun-protective skin care regimen. Fitzpatrick skin types 4 to 6 can rarely be treated with energy-based devices due to the risk of PIH. Shortening the pulse duration (less than the 50 to 500 nanosecond thermal relaxation time of melanosomes) allows for more specific pigment targeting with less thermal byproduct.^2,3 By quickly pulsing the energy, you can obtain a high peak power and generate high local temperature gradients between melanosomes and the surrounding structures. Further shortening (to picosecond and beyond) adds a high-pressure photoacoustic effect that decreases the thermal consequence on surrounding structures and increases pigment removal through physical disruption of the involved melanosomes.^11,37-38

Common theory is that longer wavelengths (e.g., 1064 nm, Q-switched neodymium-doped yttrium aluminum garnet [Nd:YAG]) penetrate deeper but also spare the epidermis (normal melanin), making it safer to treat darker skin types and deep dermal pigmentation. Q-switched ruby (694 nm) lasers, although beneficial for pigmentation due to their high reactivity on melanin, can induce permanent hypopigmentation if conservative settings on patients with the appropriate skin type are not followed. Studies have shown improvement in a variety of pigmented conditions treated with longer-wavelength lasers such as ephelides, nevus of Ota, and tattoos.³⁹ As with any laser, dyspigmentation, acneiform eruptions, petechiae and herpes simplex re-activation are risks. Combination treatment with topical brightening agents (e.g., hydroquinone, triple cream, arbutin, vitamin C, and AzA) and other cosmetic procedures described above (e.g., chemical peels) may enhance outcomes.^11,40

One author’s go-to standard treatment is low-energy, low-density 1440 nm fractional diode laser (Clear + Brilliant® Laser System) as it can treat pigmentation with little downtime or risk of PIH due to the low energy/density settings and improvements occurring slowly over time (Figure 4). Additionally, there are several studies that have shown benefit of the 1927 nm thulium fiber laser of the Fraxel® re:store Dual, FDA approved in 2009 for the treatment of melasma and pigmented lesions.41-43 Previously, this author utilized the 1927 nm thulium fiber laser (Fraxel® re:store Dual) for melasma due to its shallow penetration (200 µm depth as compared to 400-1500 µm depth of the 1550 nm erbium (Er):YAG). However, after having frequent cases of worsening or rebound, he switched to utilizing low-fluence, lowdensity treatments alone or in combination with salicylic acid peels, microneedling, or spot liquid nitrogen treatment, which ultimately gave much better initial and long-term outcomes. Additionally, melasma, and sometimes PIH (although seen more with poikiloderma than PIH), has a vascular component that needs treatment with either a pulsed dye laser (585 nm) or potassium titanyl phosphate (KTP) laser (532 nm) to improve the overall texture and tone. More studies are needed on combination treatments for melasma and PIH, as in clinical practice multiple modalities with strict topical skin care regimens are being used to give the best results with long-term outcomes (Table 3).

Lastly, although reported in the literature as effective, ablative lasers (Er:YAG 2940 nm or carbon dioxide [CO2] 10600 nm) should never be used for melasma or PIH due to the very high potential of worsening hyperpigmentation.

Radiofrequency

Radiofrequencey (RF) technology has more recently become widely used in cosmetic medicine as a result of its efficacy and safety in a variety of aesthetic conditions including melasma. RF devices produce electrical current using electromagnetic radiation in the frequency range of 3 kHz to 300 MHz.44 When the current is applied to tissue, the resistance (impedance) produces heat that induces dermal neocollagenesis. Fractional RF devices produce low-density ablation with deep penetrating energy, giving these devices the ability to improve texture, tone and color in all skin types, while also improving wrinkles, acne scars, and laxity. Since melanin is not a target of the device, there is little to no risk of hyperpigmentation unless multiple pass treatments are used with fractional devices, thereby inducing too high levels of ablation (Figure 5).

One study using a monopolar RF device (Endosit NIR®) for 6 weekly sessions to facilitate drug delivery (phytocomplex of 1% kojic acid) showed mean Melasma Area and Severity Index (MASI) score improvement from 21.3 at baseline to 15.7 after 1 month of treatment. Improvements were maintained after 6 months of no therapy (mean MASI 16.9).⁴⁴ Future studies will be investigating the use of RF devices in the treatment of melasma and PIH. One idea being researched is a combination of microneedling with fractional RF for a synergistic approach to treating melasma or PIH.⁴⁵

Conclusion

Melasma and PIH are cosmetically disturbing to patients and frustrating to physicians performing procedures, as there is currently no best single therapy that gives significant short and long-term results. Combination therapies have the potential to improve results, but long-term maintenance treatments are needed for optimal outcomes. Future direction of studies are focusing on “color blind” technologies that can treat all skin types and multiple cutaneous concerns. It is important that physicians be knowledgeable about the most current therapies such as picosecond lasers, low-fluence/low-density non-ablative lasers, fractional radiofrequency, and microneedling in order to enhance patient results and limit complications.

Figure 1a. Dyschromia from IPL on a patient with skin type 4 who was not an appropriate candidate for this treatment. Notice the broad areas of hyper and hypopigmentation.

Figure 1b. Melasma. Hyperpigmented patches in the classicdistribution of the face of a female with worsening skin complaints despite topical hydroquinone and sunscreen.

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