Melasma L81.1

Frequent, acquired, usually sharply defined, large or small-spotted, closed or reticular hyperpigmentation(melanosis) in sun-exposed areas, which either fade completely in winter or are hardly visible, but recur in loco in the coming solar season.

Characteristic is a progression over many years with marked recurrence after the first annual sun exposure.

Melasma (chloasma) is the fifth most common skin condition in Arabic-origin residents of the USA. In total, >5 million US citizens are affected.

Approximately 80-90% of those affected are of childbearing age.

Approximately 10% of those affected are men.

Most common visible pigmentary disorder during pregnancy or after taking contraceptives.

Preferably occurs in people with dark skin type (skin type III-IV according to Fitzpatrick).

The pathology of melasma is complex, although it was originally assumed that only melanocytes were affected. A more heterogeneous pathogenesis is now postulated, which involves an interplay of keratinocytes, mast cells, abnormalities in gene regulation, increased vascularization and a disruption of the basement membrane (Kwon S et al. 2016).

In detail, the following factors can be identified as having an influence:

• Genetics: 50% of patients with melasma have a positive family history.
• Pregnancy: 20% of melasma is due to pregnancy(melasma gravidarum); accentuation of the areolae mammae, the labia minora and the linea alba, which becomes the linea fusca or linea nigra.
• Endogenous hormones: melasma climacterium or exogenously supplied hormones (melasma hormonale). Also in thyroid dysfunction (patients with melasma suffer from hypo- or hyperthyroidism 4x more frequently than healthy thyroid patients).
• Medication: Long-term use of medication containing hydantoin or chlorpromazine (melasma medicamentosum). A further strong association exists with the use of antidepressants and anxiolytics as well as with the use of 5alpha-reductase inhibitors such as finasteride or dusteride.
• Cosmetics: Skin creams containing Vaseline or photosensitizing substances (Chloasma cosmeticum).
• Consuming diseases (melasma cachecticorum).
• Trauma: pressure, friction, cold, heat (melasma (chloasma) traumaticum).
• Idiopathic: see also Melasma (Chloasma ) hepaticum.

The following main pathomechanisms are observed in melasma:

• UV radiation
• Pathological activation of melanocytes
• Aggregation of melanin and melanosomes in the dermis and epidermis,
• Increased mast cell count
• Solar elastosis,
• Changes in the basement membrane
• Increased vascularization.

UV radiation:

UV radiation leads to an upregulation of melanocyte-stimulating hormone (MSH) receptors - also called melanocortin-1 receptors (MC1-R) - on melanocytes, which enables stronger binding of the hormones and thus higher melanin production (Bolognia J et al. (1989). Proopiomelanocortin (POMC) is cleaved to produce the peptides alpha-MSH and adrenocorticotropic hormone (ACTH) in response to UV radiation. When these peptides bind to and activate MC1-R, they increase the level of protein kinase A (PKA), which phosphorylates the cAMP response element(CREB). The cAMP response element is a transcription factor for MITF (= microphthalmia-associated transcription factor), an important regulator of the melanin synthesis pathway. MITF controls the expression of tyrosinase, an enzyme responsible for several steps of melanogenesis. UV has also been shown to endogenously produce 1,2-diacylglycerols (DAGs), a type of second messenger, from plasma membrane phospholipids of melanocytes via phospholipase -C and D pathways. These DAGs subsequently activate tyrosine and thus increase melanogenesis (Carsberg CJ et al. 1995). The tumor suppressor protein p53 may also play a role in UV-induced melanogenesis. This protein upregulates POMC production in keratinocytes after UVB damage, which in turn leads to increased melanin production. In addition, the tumor suppressor protein p53 also increases the transcription of hepatocyte nuclear transcription factor-1alpha (HNF-1alpha), which induces tyrosinase and thus increases melanin production.

Although these pathways physiologically induce melanogenesis in all skin, the response to UV light in melasma is exaggerated and the expression of alpha-MSH is maintained in the pigemngiations of melasma, which increases melanin production (Im S et al. (2002).

Solar elastosis and photoaging:

Solar elastosis refers to the accumulation of elastotic tissue in the dermis resulting from chronic sun exposure or photoaging. Melasma patients have been found to have a high degree of solar elastosis in the affected skin. In addition, histological analysis shows that melasma skin tends to have thicker, more corrugated and fragmented elastic fibers compared to normal skin (Kwon S et al. (2016). Ultraviolet B irradiation can stimulate keratinocytes to increase melanocyte and thus melanin production by secreting various growth factors, cytokines and hormones, including inducible nitric oxide synthase (iNOS). UVB irradiation also increases plasmin production by keratinocytes. This enzyme leads to higher levels of arachidonic acid and alpha-MSH and thus stimulates the melanin synthesis pathway (Taraz M et al. (2017). All of these factors lead to hyperpigmentation of the affected skin. In addition, it has been suggested that even visible light may play a role in the development of melasma, especially in darker skin types (Fitzpatrick types IV-VI), by interacting with the opsin-3 sensor ( Passeron T et al. (2018)

Mast cells and neovascularization:

The number of mast cells is higher in melasma skin than in unaffected skin (Videira IFS et al. 2013). UV exposure triggers the release of histamine from these mast cells, leading to downstream effects. The binding of histamine to the H2 receptor activates the tyrosinase signaling pathway and induces melanogenesis. This finding may help to explain the link between the inflammatory process in UV radiation and subsequent hyperpigmentation (Yoshida M et al. 2000). In addition, UV radiation also increases the production of mast cell tryptase, which activates precursors of matrix metalloproteinases(MMPs). These active enzymes then degrade type IV collagen and damage the basement membrane. Granzyme B, which is released directly by mast cells, further damages the extracellular matrix (ECM). Tryptase can also contribute to solar elastosis by triggering the production of elastin. Finally, mast cells induce hypervascularization, another prominent clinical finding in melasma, by secreting proteins such as vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and transforming growth factor-B (TGF-B). These angiogenic factors increase the size, density and dilation of the vessels in the affected skin and represent another therapeutic target in the treatment of melasma (Kwon S et al. 2016).

Damage to the basement membrane:

Basement membrane abnormalities play a key role in melasma pathology. UV damage activates MMP2 and MMP9 to degrade type IV and VI collagen in the basement membrane (Kwon S et al. 2016). Cadherin 11, an adhesion molecule that is upregulated in melasma skin, can then mediate the interaction between fibroblasts and melanocytes and promote melanogenesis (Kim NH et al. 2016). Cadherin 11 Involved in Basement Membrane Damage and Dermal Changes in Melasma. Acta Derm Venereol 96:635-640. cadherin 11 is also responsible for the upregulation of MMP1 and MMP2 expression, leading to further collagen degradation and accumulation of elastotic material in melasma skin. These effects may even be independent of UV irradiation (Kim NH et al. 2016).

Damage to the basement membrane also allows the movement of melanocytes and melanin granules into the dermis, which contributes to the persistent and recurrent reactivity of melasma. Similarly, restoration of the basement membrane may limit recurrence (Kwon S et al. 2016).

Dermal inflammation:

Prolonged exposure to UV radiation causes dermal inflammation and activates fibroblasts. These cells then secrete stem cell factor (SCF), which can diffuse into the overlying epidermis and stimulate melanogenesis there (Lee DJ et al. 2021). Similarly, the concentration of stem cell growth factor receptor, also known as c-kit, is upregulated in melasma lesions. When c-kit binds to SCF, it activates the tyrosine kinase signaling pathway responsible for melanogenesis characterized by increased COX-2 and prostaglandin levels, which further stimulate melanocytes (Kang HY et al. 2006).

Hormonal influence:

Estrogen has also been shown to play a role in the development of melasma, which explains the increased prevalence in post-pubertal women, oral contraceptive users and pregnant women. Studies have shown an increased number of estrogen receptors in the dermis and progesterone receptors in the epidermis of melasma lesions (Gledhill K et al. 2010; Liberman R et al. 2008). The binding of estrogen to its receptors on melanocytes and keratinocytes can activate the tyrosinase and MITF signaling pathways and thus stimulate melanin production. The role of estrogen represents a unique target for melasma therapy.

Occurs predominantly in women, very rarely also in men. First age of onset 20 - 40, on average 35 years. Pregnancy immediately preceded the onset of the disease in 40% of patients. Familial predisposition is common (>50%).

Forehead, cheeks (zygomatic region), upper lip, nose, temple and lower jaw region.

Usually sharply or reticulated, irregularly shaped, often symmetrical, brown-grey to deep brown, areal, bizarrely shaped hyperpigmentations that can confluent to larger areas. Melasma occurs particularly after UV exposure.

Analogous to the Psoriasis Area and Severity Index (PASI) the Melasma Assessment Severity Index (MASI) was developed.

Epidermal type: Melanin deposition in the basal and suprabasal layers of the epidermis, possibly extending to the stratum corneum.

Dermal type: Melanin-laden macrophages in the superficial and middle dermis.

Histochemically, an increase in the number and activity of melanocytes can be detected.

If necessary, discontinue triggering medication, e.g. hormone therapy. Check hormone status. Hyperpigmentation often recedes gradually over a period of several years after pregnancy or after discontinuation of hormonal therapy.

Sun protection: Regardless of the treatment method chosen, sun protection is essential to prevent new lesions and to avoid worsening existing melasma. The current recommendation is that patients use a broad spectrum UVA/UVB sunscreen with at least SPF 30 daily, preferably with a physical blocker such as zinc oxide or titanium dioxide. Behavioral measures such as wearing wide-brimmed hats or avoiding peak sun hours are also recommended. Recent studies also show that a sunscreen that blocks visible light as well as UV light can further enhance melasma lesions and increase the response to conventional lightening agents such as hydroquinone (Castenado-Cezares JP et al. (2014).

Camouflage: As a rule, camouflage of disturbing hyperpigmentation (e.g. Dermacolor) is the most sensible solution. Exteriors with possible irritating or light-sensitizing effects should be strictly avoided.

Therapy of 1st choice:

Hydroquinone: Depigmenting topical preparations with 2-5% hydroquinone (hydroquinone acts as a competitive substrate of tyrosinase enzymes and is to be regarded as the first-choice therapeutic agent) can lead to regression of pigmentation. However, first changes appear only after 1-2 months, success is to be assessed after 6 months. Caveat. Irregular skin pigmentation may result!

Triple cream: More effective is the combination of hydroquinone (4%) with vitamin A acid (0.05%) and a glucocorticoid to reduce irritation of the skin. This combination is available as a magistral formulation (see Hydroquinone Ointment below). Note: Instead of vitamin A acid, a 10% glycolic acid can be used (Guevara et al. 2003).

Notice. Hydroquinone treatment can lead to localized permanent depigmentation (see external ochronosis).

Rucinol: 4-n-butylresorcinol, a resorcinol derivative that targets different points of melanin synthesis.

Kojic acid is a substance naturally occurring in Aspergillus oryzae. Kojic acid inhibits the formation of free tyrosinase. It is also a free radical scavenger. Can be seen as a substitute substance to hydroquinone when the latter is not tolerated. Widely used in Asia, controversial in Europe.

Tretinoin: The efficacy of 0.05% - 0.1% tretinoin as monotherapy is proven in postinflammatory hyperpigmentation. A study is also available for chloasma, demonstrating a high likelihood of improvement.

Azelaic acid: 15-20% azelaic acid (e.g. Skinoren) can be tried for depigmentation. Results can be expected after 2-4 weeks of therapy. Currently, 20% azelaic acid is approved for the treatment of acne. Treatment of chloasma is off-label use.

Adapalene: A comparative study demonstrated superiority of 0.1% adapalene (Differin) over a 0.05% tretinoin cream.

Cryosurgery: For circumscribed foci on the face, good results have been described with superficial cryosurgery using an open spray procedure. This method requires extensive clinical experience on the part of the therapist. However, our own experience shows that it is highly efficient.

Laser: The use of lasers (ruby, YAG laser) is judged differently due to the often resulting irregular depigmentation.

Chemical peeling: Chemical peeling can be tried during the low-sun season, especially on fair-skinned patients. Particularly with 50-70% glycolic acid, possibly a combination of 10% glycolic acid and 2% hydroquinone, good clinical results can be achieved in the hands of experienced practitioners.

Liquorice extract: A locally applied liquorice extract (see belowGlycyrrhiza glabra) is commonly used in Egypt. The active agent glabridin (0.4% oily preparation) has been proven to inhibit the tyrosinase activity of the melanocytes.

Arbutin (hydroquinone-beta-D-glucopyranoside) is a plant substance from Uvae ursi folium (Bearberry plant). Chemically, arbutin is a compound belonging to the group of aryl-beta-glucosides and hydroquinones. Arbutin is less toxic than hydroquinone. Evidence of inhibition of tyrosinase has been demonstrated in one study.

Deoxyarbutin: The synthetic deoxyarbutin leads to a dose-dependent reduction of tyrosinase activity and melanin content in melanocytes.

A 10 - 20% hydroquinone monobenzylether should not be used in this disease, as there is a risk of irreversible depigmentation.

The terms chloasma and melasma are used synonymously, with the term "melasma" becoming increasingly common in the English-speaking world.

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