Melasma is a pigmented skin disease occurring on the face, the lesions are light brown to dark brown patches, often symmetrically distributed on the face, without inflammation and scaling, without obvious conscious symptoms; it is more frequent in women (90%), mainly occurs after puberty, the condition can be seasonal, often heavy in summer and light in winter, the pigmentation develops slowly and symmetrically, and can last for many years, seriously affecting the quality of life of patients.
It is difficult to treat this disease because of its stubbornness and recurrence. Treatment includes local depigmentation treatment, chemical peeling treatment, IPL, laser treatment, dermabrasion and Chinese herbal medicine treatment. The first-line medicine for melasma is currently considered to be a combination of effective topical medications (topical depigmentation therapy), mainly 3 combined therapies (HQ, retinoic acid and glucocorticoids). In this paper, the common topical topical agents are reviewed as follows.
1 Hydroquinone (HQ)
Although HQ has side effects, it is still one of the most commonly used drugs chosen by doctors to treat melasma, especially for epidermal melasma (70%), which is usually treated locally with good efficacy, while the dermal type is treated locally with poor efficacy, and the latter can be treated by chemical peeling or sometimes by laser.
Mechanism of action: HQ is a natural substrate for tyrosinase and competes with tyrosine to bind tyrosinase, thus preventing the oxidation of tyrosine to produce dopa and preventing melanin synthesis.
Efficacy: Haddad et al. conducted a randomized, double-blind, controlled study of 30 patients with melasma and found that 4% HQ resulted in 76.9% improvement in melasma [1]. Hurley et al. conducted a randomized, single-blind, half-face controlled study of 4% HQ topically alone and 4% HQ in combination with hydroxyacetic acid peels (20% for the first 2 visits and 30% for the next 2 visits) for the treatment of melasma and found that both had satisfactory There was no significant difference between the two groups in terms of skin tone brightening and melasma scores, which led to the conclusion that the efficacy of topical application of 4% HQ alone in the treatment of melasma was satisfactory. For the treatment of melasma, it is recommended that the pigmented areas be treated regularly twice a day and should be discontinued if there is no improvement in the pigmentation for 2 months, but in some patients the pigmentation started to improve only after 6 months of use [2].
Safety and tolerability: the most common reactions were mild skin irritation and sensitization, with itching, burning, irritation and allergic dermatitis of the skin, with a higher than 2% chance of skin discomfort reported in 4% HQ. Prolonged use of high concentrations of HQ (≥5%) can cause brownish yellowing and colloidal milia [3]. Bentley-Phillips and Bayles studied the safety of HQ over 6 years, with 7000 patch tests on 840 volunteers, and found that HQ in skin care products was tolerable at a range of concentrations, with 3% HQ being the most efficacious; interestingly, they found that clinical Many of the side effects observed were due to abuse, overdose and simultaneous use of multiple depigmentants [4].
2 Retinoids
Initially, retinoic acid was used in combination with HQ to improve the permeability of HQ, but later this class of drugs was found to have a pigment-reducing effect. The mechanism of action is to interfere with pigment transport, disperse pigment granules from keratinocytes, and accelerate epidermal turnover leading to depigmentation [5]. Moreover, there is evidence that it inhibits tyrosinase, dope-pigment conversion factor and melanin-induced synthesis [6].
Efficacy: Griffiths et al. compared the effect of 0.1% retinoic acid and its matrix on melasma and showed a 68% improvement in pigmentation after 40 weeks of topical retinoic acid, while the matrix group showed only a 5% improvement; and the former brightened the pigmented areas, while the latter darkened them. Skin lesion biopsies showed a 36% reduction in pigmentation with retinoic acid compared to a 50% increase in pigmentation in the stromal control group [7].Kimbrough-Green et al. randomized, controlled study of 30 patients with moderate to severe melasma using topical 0.1% retinoic acid cream for 40 weeks and topical stromal in the control group, after 40 weeks the treated group had a MASI (Melasma Area and After 40 weeks, the MASI (Melasma Area and Severity Index) score was reduced by 32% in the treatment group and 10% in the control group; 73% of the patients showed improvement in melasma and 46% in the control group; there was no skin deterioration in the treatment group and 15% in the control group; colorimetric analysis showed that the normal skin tone was brightened by 40% in the treatment group and only 4% in the control group; tissue biopsy showed Tissue biopsy showed an 8% reduction in epidermal pigmentation in the treatment group and a 55% increase in the control group. Vitamin A acid alone can improve melasma, but it can also be used in combination with HQ and skin relaxation to treat melasma [8].
Safety and tolerability: The most common side effect is dermatitis with retinoids, including burning, irritation, erythema, desquamation, and skin dryness, and because inflammation can cause hyperpigmentation, drug concentrations should be adjusted to prevent skin inflammation, especially in dark-skinned patients. Most side effects can be reversed after discontinuation of treatment, but hyperpigmentation or hypopigmentation may persist for several months [9].Kimbrough-Green et al. reported skin reactions such as erythema and desquamation in 67% of patients and only 6.7% in the basal control group.The side effects were usually mild and no patients discontinued treatment as a result and none developed hyperpigmentation. Patients on retinoic acid are more susceptible to sunburn and their skin is more sensitive to wind, cold and dry irritation [8]. Topical retinoic acid is not mutagenic or carcinogenic, however, teratogenicity has been found in animal studies, there are no adequate controlled studies in pregnant women, and there is no information on the safety of children under 12 years of age [3].
3 Corticosteroids
Mechanism of action: Melanocytes respond to various chemical mediators such as prostaglandins and leukotrienes, and corticosteroids theoretically inhibit prostaglandins and leukotrienes produced by various keratinocytes thereby affecting melanocyte function [10]; they also inhibit the metabolites of melanocytes causing inflammation, which is the mechanism by which this class of drugs is effective in the short term in hyperpigmentation-type diseases.
Efficacy: This class of drugs is often used in combination with other topical agents (e.g., retinoic acid and HQ) to treat melasma; its use alone has rarely been reported and has only been studied in small samples. kanwar et al. gave topical clobetasone propionate 0.05% to 10 patients, and pigmentation began to decrease after 2 weeks, and in 7 patients the pigmentation decreased by 80%-90% after 6-8 weeks of topical application, but the pigmentation lightening lasted for a maximum of 6 months. In some patients it lasted only 2 weeks [11].
Safety and tolerability: Patients on topical corticosteroids develop persistent erythema, pustules, and papules in the central part of the face, and the rash appears even after discontinuation of the drug, but subsides after 1-3 months. Adult female patients develop perioral dermatitis and occasionally allergic contact dermatitis; skin atrophy is also common; Kanwar et al. reported local skin atrophy and capillary dilation after 4 weeks of topical clobetasone 0.05% propionate [11]. Because of skin atrophy and other side effects, corticosteroids alone are not recommended for the treatment of melasma.
4 Combination therapy: HQ, retinoic acid and corticosteroids
The combination of topical topical agents is an effective treatment for epidermal hyperpigmentation, and the combination therapy does not destroy melanocytes and effectively inhibits melanin formation. Lai Huolong et al. applied a 1:1 mixture of 0.1% Divine cream and 0.1% hydrocortisone butyrate cream topically, together with oral vitamin C, E, and prolotherapy pills, while the control group was treated with oral medication only, and the healing rate and total effective rate were 29.5% and 91.8% in the treatment group and 22.4% and 81% in the control group, respectively, after 2 weeks of treatment [12]. Li Zong-Hua et al. applied 0.05% vitamin A acid cream and 2% HQ cream topically and took vitamins C and E orally, while the control group only took vitamins C and E orally, and the effective rate was 84% in the treatment group and 64% in the control group after 12 weeks of continuous treatment [13]. Vitamin A acid prevents HQ oxidation, promotes epidermal permeability, allows melanin clearance and promotes keratinocyte proliferation. Combination therapy has been shown to be more effective than HQ alone.4* [14] Kligman’s group formula (5% HQ, 0.1% retinoic acid and 0.1% dexamethasone acetate) for melasma in 1975 has been widely used worldwide.25* [15]. The hormones involved reduce skin sensitivity to depigmenting agents and also inhibit melanin synthesis by reducing cellular metabolism. Vitamin A acid counteracts hormone-induced skin atrophy. Then various modifications were investigated one after another. The more established triple therapy is 4% HQ (QH), 0.05% retinoic acid (RA), and 0.01% clobetasone propionate (FA). A large controlled study of HQ/RA/FA, HQ/RA, FA/RA, and FA/HQ for melasma showed that 26.1%, 9.5%, 1.9%, and 3.1% of patients in each group had complete clearing of pigmentation at 8 weeks (56 days) of treatment, respectively. The percentage of patients with complete clearing of pigmentation at 8 weeks (56 days) was 26.1%, 9.5%, 1.9%, and 3.1%, respectively; and the percentage of reduction in the extent of pigmentation was 77%, 46.8%, 27.3%, and 42.2%, respectively. Common side effects were erythema, desquamation, burning, and/or irritation, but all were mild to moderate and no skin atrophy was observed [16]. In the United States, 1260 patients with moderate to severe melasma were treated with this triple therapy and found that 75% of patients had complete clearance of pigmentation at 4 weeks and 99% at 8 weeks; 60% of patients experienced side effects, mainly skin irritation, no patients experienced skin atrophy, and a few patients experienced capillary dilation [17]. HQ, 0.1% vincristine, and 0.1% dexamethasone acetate twice daily for 5-7 weeks was effective in the treatment of melasma; and the absence of any of the three was found to affect efficacy. Decreasing the concentration reduces the occurrence of irritation reactions but also decreases the efficacy [18]. Gano and Garcia treated melasma with 0.05% retinoic acid, 0.1% clobetasone propionate, and 2% HQ for 10 weeks and found a 65% improvement in pigmentation; side effects were common but mild, and efficacy was positive even in spring and early summer when UV exposure increased [19]. In recent years, Taylor et al. randomized, double-blind, controlled study combining 3 drugs (4% QH, 0.05% RA, and 0.01% FA) and 2 drugs (HQ+FA, RA+FA, RA+HQ) for 8 weeks in 641 patients with melasma showed that common side effects were erythema, desquamation, burning, dryness, and itching, which were well tolerated by patients on all 3 combinations, and only 1 patient developed skin atrophy, and this patient was treated with FA+HQ without RA [20]. There is evidence that RA combined with hormones helps prevent skin atrophy due to topical hormones [21], but caution should still be exercised when applying hormones topically, especially on the face.Torok et al. treated 228 cases of facial melasma (173 completed) with a combination of 4% HQ, 0.05% retinoic acid, and 0.01% FA, twice daily, once a month, and discontinued when satisfactory efficacy was achieved, and if If melasma worsened, treatment was repeated for 8 weeks, with some patients repeating several courses of treatment in the 12-month study. Associated side effects occurred in 57% of patients, most commonly flaking and erythema at the treatment site, in about 1/3 of patients; the incidence of side effects increased with the course of treatment and stabilized by 6 months. No patients developed skin atrophy, thinning, rosacea, or hypopigmentation; other side effects were acne, perioral dermatitis, hyperpigmentation, and capillary dilation [22].
5 Azelaic acid (AZA)
Mechanism of action: the drug has anti-inflammatory, antibacterial, and antikeratinizing effects, competitive inhibition of tyrosinase, and antioxidant thereby reducing tissue inflammation and melanin synthesis due to oxidative stress [23].
Efficacy: Lowe et al. multicenter, randomized, double-blind, controlled study of 20% azelaic acid and its matrix for melasma, 55% of patients in the treatment group had significant efficacy at 24 weeks, compared to only 12.5% in the matrix control group [24].Verallo-Rowell et al. treated 155 patients with melasma with 20% azelaic acid and 4% HQ for 24 weeks, 84.4% of patients in the azelaic acid treatment group completed treatment and 85.9% completed treatment in the HQ treatment group; 57% of patients in the 20% azelaic acid treatment group had a grade 2 or 3 reduction in pigment intensity compared with 37% in the HQ treatment group; the extent of pigmentation was reduced more in the azelaic acid treatment group than in the HQ treatment group; overall, 20% azelaic acid was more effective than 4% HQ [25]. Another controlled study showed that 20% azelaic acid was more effective than 2% HQ and 4% HQ, which is available by prescription only, twice daily for at least 2-3 months [26].
Safety and tolerability: itching, burning, irritation, and paresthesia occur in 1-5% of patients with topical 20% azelaic acid, and other side effects such as erythema, dryness, flushing, desquamation, irritation, dermatitis, and contact dermatitis occur in less than 1% of patients, with rare asthma, vitiligo, small hypopigmented patches, hirsutism, and hair moss [26].A study by Lowe et al. found that at 4 weeks of dosing 20% azelaic acid was more effective than basal controls had more burning and irritation, but erythema, desquamation, and dryness did not differ from controls [24]; Verallo-Rowell et al. treated 77 patients with melasma with 20% azelaic acid and 14.3% experienced mild, temporary, localized irritation, 6.5% had significant irritation, and only 2.6% had erythema and desquamation [25].Balina and Graupe treated 122 patients with melasma with 20% azelaic acid, 18 cases showed local irritation (14.8%) and the majority of irritation was mild and transient [26].
Other topical agents: tretinoin, 4-isoflurane propyl catechol (4-IPC), N-acetyl-4-sulfo-cysteaminophen, adapalene, flavonoids from licorice root, such as photoglycyrrhizin and isoglycyrrhizin, and 2-phospho-L-vitamin C have been reported to have topical depigmentation effects, but since there are few relevant studies and most of them are small samples, their However, since there are few relevant studies and most of them are small sample studies, clinical use is still pending.
6 Chemical peeling treatment
The mechanism of chemical peels is to remove melanin, not to inhibit melanocytes or melanin synthesis. While lighter-skinned patients usually tolerate peels, darker-skinned patients with peels may experience increased PIH (postinflammation hyperpigmentation) and melasma and should therefore be chosen with caution [27]. Complications of peels increase with the depth of the peel, with superficial peels having the least side effects, but still with a risk of hyperpigmentation. Common side effects include persistent post-peel erythema and infections, but infections are rare [28]. Peeling agents that have been studied for melasma include salicylic acid [27], trichloroacetic acid [29], retinoic acid [30], resorcinol [31], and fruit acids [32-34], but fruit acids are the most popular, probably because they are easy to handle, generally safer, require little downtime, rarely show scarring, and are rare for post-peel hyperpigmentation or persistent erythema [34]. There are fewer studies related to other peeling reagents, and they are all small sample studies.
Fruit acid peels: fruit acids are often present in whitening products at 10% concentration, and their high concentration (>20%) can be used as a peeling agent. lim and Tham conducted a single-blind, half-face controlled study of 10 Asian female melasma patients with a single chemical peel (20%-70%) every 3 weeks on one side of the face + daily topical application of 2% HQ and 10% fruit acids on both sides, in the treatment group. In the control group, only 2% HQ and 10% fruit acids were applied topically to both sides of the face, and the efficacy was judged at the end of the treatment, with the treatment group outperforming the control group. There was irritation and skin redness after each peel, and one patient had a burning sensation and caused temporary hyperpigmentation after 20% fruit acid peel, which subsided after 2 months; there was no scarring or aggravation of melasma [33].Javaheri et al. studied peels for 25 cases of melasma, and 91% of patients improved at the end of the third peel, with the epidermal type having a better outcome than the mixed type; one patient had a pale Sarka et al. treated 40 Indian patients with moderate to severe melasma with fruit acid peels (30% fruit acid for 3 peels and 40% fruit acid for 3 peels) + modified Kligman’s HQ formula (MKF) in the treatment group and MKF alone in the control group, with no statistical difference in efficacy between the 2 groups at 12 and 21 weeks of treatment. There was no statistical difference between the two groups, but 80% of patients in the treatment group felt excellent and 60% of patients in the control group felt excellent. side effects were mild in both groups, with mild erythema and epidermal peeling in almost all peel patients; two peelers developed PIH, which later subsided with betamethasone dipropionate 0.05% [35]. Xiang Leihong et al. treated 64 patients with melasma with 20%, 35%, 50%, and 70% fruit acids and showed that the epidermal melasma was 75.75% efficient and the mixed type was 40.00% efficient, and all patients tolerated 70% fruit acids [36].
In conclusion.
The mechanism of melasma formation has not been fully elucidated, and the complex process of pigment formation includes tyrosinase activity, the structure of melanosomes and their formation and transport in melanocytes. In conclusion, treatments that act on multiple stages of melanosome synthesis are more effective than those that only act on a single stage.
The first line of treatment for melasma is a combination of effective topical agents, mainly a modified triple therapy (4% HQ, 0.05% retinoic acid and 0.01% clobetasone propionate). When the patient is allergic to these components or they are not available, other 2-combination therapies (2% HQ + 10% GA, etc.) or single agents (4% HQ, 0.1% retinoic acid, or 20% azelaic acid) can be considered. These methods together with topical sunscreens with UVA and UVB protection are the most commonly used to treat epidermal melasma. IPL is effective, but must be combined with topical agents such as HQ, retinoic acid and corticosteroids, and it is very important to instruct patients to avoid light and use sunscreen regularly. Very rarely laser is used to treat melasma, and if it is chosen, skin type should be considered. De-stressing the liver, nourishing the liver and kidney, strengthening the spleen and nourishing the blood, and always activating blood circulation and removing blood stasis are widely used in the clinical treatment of melasma.