Peeling as a component of combination therapy for melasma

Sabine Zenker, MD, dermatologist (Germany)

Melasma is a difficult-to-treat, persistent discoloration of dark skin, usually found in dark-skinned women and women who have reached puberty. The disease is characterized by brown spots, mainly on the face or other areas exposed to the sun. The etiology can be different: excessive exposure to ultraviolet radiation, hormonal disorders, genetic predisposition and side effects of medications. More recently, the role of estrogen in melasma has become clearer as the protein-coupled estrogen receptor (GPER) appears to enhance melanin synthesis by increasing tyrosinase activity. The scientists concluded that GPER is therefore a potential drug target for the treatment of chloasma. M. Rostami Mogaddam et al. found that there is a relationship between autoimmune thyroid function and melasma: patients with melasma, compared with controls, had a higher incidence of thyroid dysfunction and positivity for thyroid peroxidase antibodies. They also found that there was a significant association between low zinc levels and the occurrence of melasma.

Pathology Clinic

Clinically, melasma manifests itself in the form of many spots located closer to the center of the face, as well as on the neck, décolleté, and possibly on the ends of the arms and legs. The diagnosis is made on the basis of examination, including under a Wood's lamp: epidermal melasma is quite pigmented and gives a positive test result under the lamp, dermal melasma is usually colored grayish and gives a negative examination result. Histological examination reveals increased levels of melanin in the epidermis, dermis, or both layers of the skin.

Melasma is a consequence of hyperfunction of melanocytes, which leads to excessive deposition of melanin in the epidermis and dermis. In addition, in some cases, this disease is accompanied by rosacea, as well as a typical sign of skin photoaging - solar elastosis; Occasionally, perivascular lymphohistiocytic infiltration may occur. Melasma not only has a significant impact on the aesthetic appearance of patients, but also, of course, on their psychological state.

Unfortunately, treating melasma effectively and safely remains a major challenge. In addition, it is necessary to develop an effective skin care program for such patients, since the disease is prone to recurrence.

An abbreviated Cochrane Collaboration review published in J Am Acad Dermatol in 2014 reported that “meta-analysis is not possible due to heterogeneity among treatments” and “randomized controlled trials with well-defined study populations and long-term outcomes are needed to develop a consensus.” As a dermatologist who suffers from this condition myself, I began my clinical research into topical treatments back in the late 1990s. My goal was to find a safe and effective method, as well as an optimal therapeutic approach for the long-term management of melasma-prone skin.

Topical treatment

There are several treatment concepts for melasma. In topical treatment, the strategy is to effectively control and suppress excess melanogenesis using topical medications.

Tretinoin

Before melanin formation, the transcriptional expression of tyrosinase can be affected or the level of melanogenic mediators (α-MSH) can be reduced. A good example of a topical medication here is tretinoin, a carboxylic acid form of vitamin A. All-trans retinoic acid (ATRA), as it acts on retinoid-activated transcription factors, inhibits melanocyte development and melanogenesis, stimulates the differentiation of melanocyte precursors and removes differentiated melanocytes through its exfoliating ability. Other derivatives are often used in medicinal cosmetics, such as retinol palmitate (an ester of retinol and palmitic acid) and retinol (vitamin A, axerophthol).

Hydroquinone

A common strategy to combat melasma is to block the main enzymes involved in melanogenesis, tyrosinase and peroxidase, during melanin synthesis, as well as inhibit the ROS scavenger. The gold standard here is undoubtedly hydroquinone (HQ). This drug is well known for its suppressive effect on melanin synthesis. Because its hydroxyphenolic compound is structurally similar to melanin precursors, its mode of action is predominantly defined as a competitive tyrosinase inhibitor. Hydroquinone affects the formation of melanin, as well as the degradation of melanosomes.

The effectiveness of hydroquinone depends on the dose, as do the side effects of its use. Typical side effects tend to be mild skin irritation or contact dermatitis, confetti-like hypopigmentation, exogenous ochronosis (seen in South Africa where high concentrations of non-pharmaceutical grade hydroquinone are used). To date, there have been no documented cases of malignant neoplasms associated with the use of hydroquinone.

Arbutin

Another active substance is arbutin. It is a naturally occurring β-D-glucopyranoside obtained from the leaves of various berries (bearberry, cranberry, etc.). It reduces tyrosinase activity without affecting the expression of messenger RNA (mRNA), inhibits the activity of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) polymerase (pmel17/silver protein) and has an inhibitory effect on melanosome maturation. Its effectiveness also depends on the dose.

Kojic acid

Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone) is a substance synthesized by fungi or bacteria (Acetobacter, Aspergillus, Penicillium). Inhibits free tyrosinase by chelation of copper. Kojic acid is highly irritant, has limited penetration into the skin due to hydrophilicity and also has a dose-dependent effect. Azelaic acid, originally derived from Pityrosporum ovale and effective for acne and rosacea, can also be used to inhibit melanin production.

Phenylethyl resorcinol is a potent non-irritant antioxidant that can reduce melanin synthesis and suppress inflammation by inhibiting cox-II-tyrosinase and other factors that stimulate inflammatory melanin.

Ascorbic acid

Ascorbic acid prevents melanin synthesis, interacts with copper ions in the active site of tyrosinase and reduces dopaquinone by blocking the oxidation of DHICA. One example of an agent with peroxidase inhibitory properties is methimazole, an antithyroid agent belonging to the thioamide group, which has an inhibitory effect on the oxidation of both fungal tyrosinase and 5,6-dihydroxyindole (DHI) peroxidase to produce hydrogen peroxide (H2O2) as a by-product product.

After suppression of melanogenesis, inhibition of melanosome transfer and melanin dispersion are two main strategies to reduce unwanted pigmentation and melanin content in the skin. The basis for topical melasma therapy is linoleic acid, soy, alpha hydroxy acids (AHA) - glycolic , lactic acid or others (mandelic, citric acid, etc.), which exfoliate the skin. Peeling with alpha hydroxy acids leads to thinning of the stratum corneum and melanin dispersion, and also improves the penetration of other active substances. In addition, alpha hydroxy acids, known for their antioxidant, anti-inflammatory and anti-comedogenic effects, improve overall skin quality. The combination of glycolic and lactic acid with hydroquinone also inhibits melanin production and is very effective in treating melasma. Niacinamide has anti-inflammatory properties and may reduce melanosome transfer. Beta hydroxy acids, such as salicylic acid, loosen keratinocytes and thereby remove melanin.

Possibilities of peelings as a therapy for melasma

Given the potential of the topical medications mentioned above, combining them for topical treatment of melasma makes significant sense. The goal is to achieve controlled skin renewal to eliminate unwanted hyperpigmentation and control the formation of melanin.

In addition, any treatment should begin with adequate skin care, which should be selected individually. Therapeutic cosmetics play an important role. They contain biologically active ingredients that increase skin moisture and hydration, protect, prevent oxidation and inflammation, and also improve metabolic processes in cells. Traditional topical medications, hydroquinone, tretinoin and corticosteroids can be found in triple combination cream formulations or Kligman's formula and are quite suitable for this purpose.

According to several factors, such as the characteristics and severity of melasma formation, duration of the disease, possible treatment options (recent treatment or treatment performed many years ago), skin type and phototype, as well as the patient's expectations and considerations regarding the effectiveness and timing of therapy, I decide which working products to use and formulate the appropriate topical preparations individually. There are two strategic ways to select topical medications:

• higher concentrations of specific agents such as retinoic acid or exfoliants. The greater therapeutic potential of prescription drugs will coincide with more effective treatment outcomes, but may also lead to increased required interruption of their use;
• alternatively, prolonged exposure to hydroquinone should be avoided and maintenance therapy with alternative agents should be considered. A good example of a treatment option without hydroquinone is special combination peels. Typical working agents responsible for the brightening effect may be kojic acid, alpha-arbutin, azelaic acid, tyrosinol complex, vitamin C, niacinamide, retinyl palmitate and salicylic acid. The duration of action of such peels depends on all the variables mentioned above - the severity of melasma, skin type and condition, etc.

It is important to understand that favorable treatment results can be obtained using only such combined peels. These treatments are very suitable for treating less severe cases and for maintaining the effects of medical treatments. However, in many cases, melasma requires more serious treatment.

Combined treatment: peelings + active substances

Medical chemical peels for the treatment of melasma are typically formulated individually based on the practitioner's experience by combining various agents, prescription and non-prescription. The goal is to combine the effect of a controlled, deeper chemical peel with the effect of local lightening. This is why it makes sense to tailor your treatment protocol individually, combining the effect of various substances with the ability of the peel to controllably lighten and cleanse the skin.

Typical medications included in these programs are hydroquinone (1,4-dihydroxybenzene), tretinoin (trans-retinoic acid) with salicylic acid, lactic acid, AHAs, and ascorbic acid. The overall strength of this treatment can be compared to a medium depth peel. By changing the working agents, their concentrations, delivery method (for example, solution or mask), exposure time, and the number of layers applied, this method is adapted to each patient.

The decision to prescribe any treatment method must be made individually for each patient in accordance with the indications. In addition, you need to create a skin care plan before and after peeling. The patient should understand that melasma-prone skin requires an individual “diet”, which means that when choosing the appropriate skin care product, one must be very careful, as many ingredients can increase the risk of the occurrence, exacerbation or recurrence of post-inflammatory hyperpigmentation . Therefore, any patient with melasma should be given individual instructions on skin care, as well as recommended to use SPF adapted to their skin type every day for a year. It should also be warned that risk factors include topical application and ingestion of hormones.

Additionally, educating our patients is key to better compliance and success of this treatment. Before starting treatment, we need to compare different treatment options, and then tell us what results we can get, and explain to the patient that it is impossible to completely cure melasma, but it is possible to successfully stop this skin disease. Such patients need to be offered a realistic and effective treatment concept, as this affects their emotional state.

In addition, it is important to highlight the fact that every patient must understand that they must be careful when choosing skin care products and use SPF tailored to their skin type every day for a year. The patient must also understand that the treatment option may not work: there is a high risk of exacerbation or induction of post-inflammatory hyperpigmentation and relapse of the disease.

Summing up

As we have already discussed, there are various topical treatment options described in the literature and clinically used for many decades. My personal experience of 15 years with topical dermatological treatments to treat melasma shows that such methods can be very effective in both treating and preventing recurrence. But at present there is no sufficient evidence base for the effectiveness of many of the procedures being carried out, there is no standardized system for assessing results, and existing studies are of insufficient duration and volume. As an abbreviated Cochrane Collaboration review published in J Am Acad Dermatol in 2014 stated, to find consensus on how best to treat melasma, “randomized controlled trials with well-defined study populations and long-term outcomes are needed.”

Lightening melasma pigmentation with peelings with the addition of over-the-counter and prescription substances that act on different stages of melanogenesis is an effective and safe method of treatment with a long-term perspective.

First published in ​"Les Nouvelles Esthétiques Ukraine" No. 2 (114) /2019