The Pathophysiological Mechanism of “King of All Freckles” - Melasma and Progress in Its Drug Treatment

Melasma is a chronic hyperpigmentary skin disease commonly seen in Asian and Latin American women of reproductive age with Fitzpatrick skin types III to VI. Clinically, it manifests as symmetrical, butterfly-shaped, or irregular brownish-yellow patches distributed on the face. The etiology of melasma is complex, involving genetic factors, estrogen, ultraviolet light, pregnancy, among others. Additionally, sun exposure, mental stress, staying up late, and fatigue can exacerbate the condition. Its pathophysiological mechanism is intricate, correlating with the hyperactivity and aggregation of melanocytes, inflammation, vascular proliferation, and damage to the basement membrane. Currently, there are numerous treatment options available in clinical practice, often involving a combination of therapies, of which pharmacological treatment is the primary method. Both topical and oral medications primarily target tyrosinase inhibitors, aiming to achieve therapeutic effects by inhibiting tyrosinase synthesis and melanosome transportation.

Pathophysiological Mechanism of Melasma

1. Activation and Aggregation of Melanocytes

Studies have shown that the activation of melanocytes and the accumulation of melanin in the epidermis and dermis are significant pathological features of melasma. The autophagy of melanocytes and keratinocytes affects skin pigmentation, and autophagy defects can regulate melanosomes to promote melanocyte activity and melanogenesis. Autophagy in the skin is crucial for homeostasis, antigen presentation, repair of cellular damage, and regulation of cell turnover, which can be induced by oxidative stress, ultraviolet radiation, and other factors. Microtubule-associated protein 1A/1b-light chain 3 (LC-3) is the most important marker of autophagy. Comparative evaluation of LC-3 in melanocytes, keratinocytes, and dermal fibroblasts in facial melasma lesions and their adjacent unaffected skin tissues has revealed reduced expression of LC-3 in melanocytes in the basal layer of melasma lesions. Stem cell factor (SCF) is a paracrine factor produced by fibroblasts, and its receptor c-kit is expressed on melanocytes. The binding of SCF to c-kit activates tyrosine kinase, playing a role in melanogenesis. Studies have found significantly reduced expression of Wnt inhibitory factor (WIF-1) in keratinocytes and fibroblasts in the lesions of melasma patients. Knocking out WIF-1 in fibroblasts can increase tyrosinase expression and promote melanosome transfer to keratinocytes. The decreased expression of WIF-1 can stimulate melanogenesis and participate in the development of melasma by upregulating the Wnt signaling pathway. Additionally, studies have found that in cultured human melanocytes and artificial skin, fibroblasts from melasma lesions can promote melanin production and stimulate the expression of nerve growth factor-β, suggesting that fibroblasts may play a role in the pathogenesis of melasma by activating melanocytes.

2.Increase in Mast Cells and Solar Elastosis

Comparative studies have found that the number of mast cells in the lesions of melasma is significantly higher than in the skin surrounding the lesions. Moreover, the degree of elastosis in the lesions of melasma is notably higher than in the surrounding skin. Mast cells are cells that mediate inflammatory responses and can secrete inflammatory factors such as histamine and interleukins. In vitro studies have revealed that after treatment of melanocytes with histamine, the expression of tyrosinase (TYR), tyrosinase-related protein 1 (TRP-1), tyrosinase-related protein 2 (TRP-2), and growth differentiation factor 15 (GDF-15) increases. When the GDF-15 gene is silenced, the TRP-1 and TRP-2 that mediate histamine-induced tyrosinase expression are inhibited, indicating that GDF-15 promotes histamine-induced melanogenesis. Additionally, mast cells exhibit increased histamine release under ultraviolet radiation, and histamine receptor-2 mediates the stimulation of melanocyte proliferation and migration through protein kinase α activation.

3.Vascular Proliferation and Basement Membrane Disruption

The blood flow and vessel diameter in the lesions of melasma are greater than in normal skin. Mast cells can induce vascular proliferation by secreting angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and transforming growth factor-β (TGF-β). The increased expression of VEGF in keratinocytes may be the primary angiogenic factor responsible for the vascular changes in melasma. VEGF binds to specific receptors located on endothelial cells that produce endothelin-1. Studies using an in vitro coculture model of microvascular endothelial cells and melanocytes have found that endothelin-1 released by microvascular endothelial cells can increase tyrosinase levels by activating endothelin receptor B, mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and p38, thereby inducing melanogenesis and promoting pigmentation. VEGF can also partially regulate pigmentation by upregulating the expression of protease-activated receptor-2.

It has been confirmed that there is damage to the basement membrane in the lesions of melasma. Research on the ultrastructure of the basement membrane in melasma reveals that the dense layer of the basement membrane is damaged, with widened gaps, reduced density, and thinning. Anchor fibers in the lucid layer are lost, and cellular organelles in melasma skin, such as mitochondria, microvesicles, endoplasmic reticulum, Golgi apparatus, and melanosomes, are evident. The maturity of melanosomes is also higher than in adjacent skin. PAS staining of the basement membrane shows that type IV collagen is the main component. Studies have demonstrated that compared to normal skin surrounding the lesion, there is an increase in melanocytes below the dermal-epidermal junction in melasma lesions, and the expression of type IV collagen is significantly reduced in the affected skin. At the same time, it was found that matrix metalloproteinase-2 (MMP-2), which degrades type IV and type VI collagens, is significantly upregulated in the affected skin. Recent studies have also found increased expression of Cadherin 11 in melasma lesions. Cadherin 11 is an adhesion molecule that promotes melanogenesis by mediating the interaction between fibroblasts and melanocytes. It can also upregulate the expression of MMP1 and MMP2, further degrading collagen in melasma skin. Damage to the basement membrane prompts melanocytes and melanin granules to descend into the dermis, thereby contributing to the persistence and recurrence of melasma.

Treatment of Melasma with Medication

Currently, there are various treatment methods for melasma, including but not limited to sun protection. Combination therapies are generally used, among which medication is the primary approach, encompassing topical and oral medications.

1.External Medications

① Hydroquinone and its derivatives. Hydroquinone is the most commonly used decolorizing agent. It inhibits melanin synthesis by competitively inhibiting the activity of tyrosinase, while also inhibiting the synthesis of melanocyte DNA and RNA to damage melanocytes. It is a first-line external medication for melasma. The clinically commonly used concentration is 2% to 5% hydroquinone cream. The higher the concentration, the stronger the decolorizing effect, but the greater the skin irritation, which may cause itching and burning sensation, or even contact dermatitis. Long-term high-dose use can lead to exogenous pigmentation and colloidal miliaria-like lesions on the skin. Therefore, combination therapy with other external medications is often adopted in clinical practice. Arbutin and deoxyarbutin are glucoside derivatives of hydroquinone, which have less skin irritation than hydroquinone and can also be used clinically for the treatment of melasma.

② Azelaic acid. Azelaic acid is a skin decolorizing agent that acts on the tyrosinase of functionally hyperactive melanocytes, inhibits mitochondrial oxidoreductase and DNA synthesis, produces cytotoxic effects, and inhibits proliferation. It can also inhibit reactive oxygen species, reduce oxidative reactions in the inflammatory process, and has anti-inflammatory, antibacterial, and depigmenting effects. The clinically commonly used concentration is 15% to 20% cream, applied twice daily for about 6 months. It is recommended for patients who are intolerant to hydroquinone treatment and require long-term medication. Common adverse reactions include mild local irritation, erythema, desquamation, and burning sensation. Azelaic acid is one of the few skin lightening agents that can be used for melasma during pregnancy.

③ Tretinoin (Vitamin A acid). Tretinoin can interfere with the normal metabolism of melanin, accelerate epidermal renewal, shorten its turnover time, and promote the shedding of keratinocytes, thereby removing melanin granules in keratinocytes. It can also reduce tyrosinase activity, inhibit dopachrome tautomerase and melanin synthesis. When combined with other drugs, it can promote their penetration and improve their efficacy. The clinically used concentration is 0.05% to 0.1%, and it generally takes 6 months to see results. Due to the long treatment time, skin irritation reactions such as erythema, desquamation, and post-inflammatory pigmentation are prone to occur. Therefore, combination therapy is generally recommended instead of using tretinoin alone.

④ Chemical peeling agents. Commonly used drugs include glycolic acid (GA), salicylic acid, trichloroacetic acid (TCA), etc. The principle is to remove the melanin on the skin surface, causing epidermal and dermal reconstruction, without inhibiting melanocyte activity and melanin synthesis. It can be used to treat refractory epidermal melasma and promote the penetration of other external medications. Common clinical adverse reactions include erythema, desquamation, edema, and stinging sensation. It should be noted that patients with darker skin are prone to melasma exacerbation or post-inflammatory pigmentation.

⑤ Combination therapy. Due to the complex etiology of melasma and its chronic, recurrent nature, treatment should consider both effectiveness and patient compliance. Currently, combination therapy is often adopted clinically. The commonly used external medication recommended by the US FDA is the "triple cream therapy," which is a mixture of 4% hydroquinone, 0.01% fluocinonide, and 0.05% tretinoin. The principle is that hydroquinone competitively inhibits tyrosinase activity and melanosome synthesis; glucocorticoids inhibit prostaglandins or cytokines in epidermal cells, have anti-inflammatory and melanocyte metabolic inhibitory effects, and can reduce skin reactions caused by hydroquinone and tretinoin, but their effect is short-lived; tretinoin avoids the oxidation of hydroquinone, increases its permeability, and inhibits melanin production.

2. Oral/Injection Administration of Drugs

① Tranexamic. Tranexamic is an antifibrinolytic agent that can inhibit the binding of plasminogen to keratinocytes, reduce the synthesis of arachidonic acid and prostaglandins, thereby decreasing the activity of tyrosinase. It can also competitively inhibit the activity of tyrosinase. Microinjection of tranexamic into skin lesions is a commonly used treatment method for chloasma, with 4mg/mL solution most frequently administered once every 1 to 2 weeks. Adverse reactions are mainly related to the injection itself, including temporary pain, erythema, edema, ecchymosis, wheals, and irritant dermatitis. Oral administration of tranexamic is also a convenient and effective treatment for chloasma, but requires a course of more than 6 months.

② Vitamins. Vitamin preparations commonly used in the clinical treatment of chloasma include vitamin C and vitamin E, both of which are antioxidants. Vitamin C can reduce H2O2 produced by the body's metabolism, reducing the oxidation of melanin during its catabolic process. Vitamin E, also known as tocopherol, provides active hydrogen atoms to bind to oxygen radicals, thereby inhibiting lipid peroxidation. Both vitamins can work together to resist ultraviolet rays and prevent pigmentation.

③ Glutathione. Glutathione is an endogenous antioxidant that can inhibit tyrosinase, reduce inflammation, and shift the production of black or brown eumelanin to the production of yellow-red pheomelanin. It can be administered orally or intravenously, and is often used in combination with vitamin C.

To further enhance the therapeutic effect of chloasma treatment, reduce adverse reactions and recurrence rates, the integration of traditional Chinese and Western medicine has become a trend in treatment. For mild cases, external application of hydroquinone and Sibai Quban ointment are the main methods; for moderate to severe cases, a combination of oral and external application of tranexamic with traditional Chinese medicine (TCM) treatment based on syndrome differentiation can be used. The basic principles of TCM treatment include soothing the liver, relieving depression, nourishing qi and strengthening the spleen, and nourishing the liver and kidneys. Blood stasis, as a major pathological factor in chloasma, should be addressed throughout the treatment, thus requiring the addition of blood-activating and stasis-resolving herbs regardless of the syndrome type. In addition, depending on the condition, traditional Chinese medical treatments such as herbal face masks, scraping (gua sha), cupping, acupuncture, as well as comprehensive therapies such as chemical peeling, photoelectricity therapy, and "mesotherapy" can be applied to achieve internal and external treatment and comprehensive management of the condition.

References:

[1] Zhou Na, Liu Zhenfeng, Tao Jingjing, Liu Runying, Yang Bin. Pathophysiological Mechanisms and Related Treatment Progress of Chloasma [J]. Journal of Dermatology and Venereology, 2022, 29(02): 165-168.

[2] Xia Zhikuan, Zhang Jinxia, Yang Rongya. New Progress in Drug Therapy for Chloasma [J]. Chinese Journal of Aesthetic Medicine, 2019, 28(05): 22-24.