|Year : 2014 | Volume
| Issue : 2 | Page : 70-80
Recent advances in melasma
Manas Chatterjee1, Biju Vasudevan2
1 Department of Dermatology, Command Hospital, Kolkata, West Bengal, India
2 Department of Dermatology, INHS Asvini, Mumbai, Maharashtra, India
|Date of Web Publication||15-Dec-2014|
Department of Dermatology, Command Hospital, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Melasma is one of the most common pigmentary disorders worldwide with a still unresolved pathogenesis and treatment continues to be challenging. Increased sun exposure and genetic factors are considered the two most important etiological factors. Estrogens, progesterones and increased melanocyte stimulating hormone are also involved. Melasma treatment can be very frustrating as many modalities can turn out to be ineffective. Dermal and mixed variants are quite resistant to therapy. Most patients seek medical help much after the onset of the condition, making treatment even more difficult. Sunscreens and topical depigmenting agents remain mainstay of therapy. Chemical peels and light sources are beneficial as adjuncts. There have been numerous advances in the understanding and management of melasma. This review attempts to look at these newer vistas in melasma. Literature search for the review was done from PubMed, the Cochrane Library, MEDLINE and Embase using the key word "melisma," "melasma pathogenesis" and "melasma treatment."
Keywords: Hydroquinone, lasers, medical, melasma, pigment
|How to cite this article:|
Chatterjee M, Vasudevan B. Recent advances in melasma. Pigment Int 2014;1:70-80
| Introduction|| |
The pathogenesis of melasma remains poorly understood and its treatment continues to be challenging. With approximately 10% cases occurring in men, it has become a universal, across the gender disorder. The disease prevalence among Asians is about 40% in females and about 20% in males.  Melasma is the most common pigmentary disorder in India, with incidence of approximately 10%.  It is also found to occur at a younger age among Indians.  There have been numerous advances in the understanding and management of melasma. This review attempts to look at these newer vistas in melasma. Literature search was done from PubMed, the Cochrane Library, MEDLINE and Embase using the key word "melisma," "melasma pathogenesis" and "melasma treatment."
| Pathogenesis|| |
Multiple factors have been incriminated in the pathogenesis of melasma. The current concepts include.
In melasma, there is no increase in the actual number of melanocytes.  Melanocytes in lesional melasma skin are highly dendritic, and shows increased DNA synthesis in electron microscopic studies. Melanocytic activity is exaggerated resulting in increased formation, melanisation and transfer of melanosomes to keratinocytes. The melanosomes are also increased in size.  Higher amounts of melanin are found in the epidermis and within macrophages in dermis. Increased melanogenesis - associated genes and proteins are also found in the epidermis. In addition, there are high levels of tyrosinase-related protein 1 (TRP-1) mRNA indicating a regulating mechanism at the mRNA level. 
Basal membrane damage
This leads to falling off or migration of active melanocytes and melanin into the dermis and may be responsible for the persistent hyperpigmentation in melasma.
Dermal inflammation caused by ultraviolet (UV) irradiation may activate fibroblasts, resulting in up-regulation of stem cell factors leading to increased melanogenesis. 
Interactions between altered cutaneous vasculature and melanocytes influence the development of hyperpigmentation in the overlying epidermis. There is a significant increase in both number and size of the dermal blood vessels in melasma lesions.  Melanocytes respond to angiogenic factors as they express increased number of vascular endothelial growth factor (VEGF) receptors. 
It has been reported that lesional melasma skin has increased expression of nerve growth factor receptors and neural endopeptidases thus paving way for various neural peptides to act as etiological factors. 
Stem cell factor, c-kit and mast cells may also have probable roles.  Tranexamic acid has been found to prevent binding of plasminogen to keratinocytes, leading to a possible mechanism for treatment of melasma. 
| Aetiological Factors|| |
Increased sun exposure and genetic factors are considered the two most important etiological factors. UV rays lead to lipid peroxidation of cellular membranes resulting in free radical production and finally increased melanin production. All the wavelengths emanating from sunlight, including visible light can induce melasma.
Familial occurrence and increased incidence in certain races aid the suspicion of an increased role for genetics. Genetic predisposition exists and is more common in women, with about 30% of females reporting a positive family history. Down regulation of H19 gene which can be detected by microarray analysis of hyperpigmented skin from melasma patients could be a torch bearer for further genetic research.  AGOUTI proteins which compete with α-melanocyte-stimulating hormone (MSH) in melanocortin 1 receptors (MC1-R), may also provide physiopathological basis for understanding the role of MSH/MC1-R system in the pathogenesis of melasma. 
Though considered physiological in pregnancy, it hardly regresses 100% after delivery. Estrogens, progesterones and increased MSH are all incriminated. The reduced incidence in postmenopausal women and in men supports the role of hormones. Estrogen acting on estrogen receptors present on melanocytes may stimulate these cells to produce extra melanin. Increased luteinizing hormone with lower serum estradiol due to ovarian dysfunction could also be a reason.
Thyroid dysfunction and anti-thyroid antibodies may sometimes be associated with melasma.
In one-third of women and more than 75% of men, no specific cause can be identified. Idiopathic melasma in women is proposed as being secondary to subclinical ovarian dysfunction with end organ hyper-responsiveness. 
| Clinical Features|| |
The centrofacial variant is described as being most common worldwide [Figure 1]. However, in India the malar region is more frequently involved (73%).  Rarely other sun-exposed regions like extensors of the forearm may be involved.
|Figure 1: Distribution of melasma: (a) Centro-facial, (b) mandibular, (c) malar, (d) forearm|
Click here to view
The classification of melasma into the four histopathological types aided by Wood's lamp examination is not entirely fool proof. There may not always be a good correlation between Wood's lamp findings and histopathology. A recent classification divides melasma into transient and persistent variants depending on natural history. Lesions disappearing within a year of stopping any risk factors like oral contraceptive pills or after pregnancy is classified as transient while lesions present even after 1 year of absence of any risk factors is called persistent. The persistence is due to persisting sun exposure.
The severity of melasma disease is usually assessed by the Melasma Area and Severity Index (MASI).  Recently a modified MASI has been proposed by removing the component of homogeneity which is difficult to assess. This score ranges from 0 to 24. The calculation is as follows:
• 0.3 (A × D) forehead + 0.3 (A × D) left malar region + 0.3 (A × D) right malar region + 0.1 (A × D) Chin where: Area: 0 = absent, 1= ≤10%, 2 = 10-29%, 3 = 30-49%, 4 = 50-69%, 5 = 70-89%, 6 = 90-100%, darkness: 0 = absent, 1 = slight, 2 = mild, 3 = marked, 4 = severe. 
| Investigations|| |
Dermoscopy of melasma lesions demonstrate a fine brown reticular pattern superimposed on a background of faint light brown structureless areas. This can be differentiated from exogenous ochronosis that shows dark brown globules and globular structures on diffuse brown background.  Objective measurement of the melanin content can be done with an instrument called Mexameter and also by confocal microscopy.
The Mexameter is a narrowband reflectance spectrophotometer which contains 16 diodes emitting light of three wavelengths: 568 nm (green), 669 nm (red), and 880 nm (infrared). Melanin which is responsible for the pigmentation in melasma absorbs all wavelengths but more so in the red and infrared spectrum. The melanin index is calculated from intensity of absorbed and reflected light at the wavelengths 669 nm and 880 nm. The Mexameter can grade the degree of hyperpigmentation in melasma from white (1) to black (1000). 
In vivo reflectance confocal microscopy (RCM) is a noninvasive imaging tool which provides real-time images of skin at resolutions almost reaching histological standards. Melanin having a strong contrast to rest of the skin is easily differentiated by this investigational tool. In the epidermis, RCM shows significant increase in the hyperrefractile cobblestoning cells corresponding to hyperpigmented basal keratinocytes on histology. In the dermis, melanophages are represented by plump bright cells. It is an innovative way to classify melasma into epidermal and dermal based on topographical pigment changes.  RCM analysis can also help monitor the response to therapy. 
| Treatment Modalities|| |
Melasma treatment can be very frustrating as many modalities can turn out to be ineffective. Dermal and mixed variants are quite resistant to therapy. Most patients seek medical help much after the onset of the condition, making treatment even more difficult.
| Medical Management|| |
Medical management of melasma comprises mainly of sunscreens and skin lightening agents.
Sunscreens are an important part of treatment strategy in melasma. All wavelengths of sunlight, including the visible spectrum, are capable of inducing melasma. Most commercial sunscreens do not block wavelengths >380 nm and therefore melasma patients are not protected from the longer UVA wavelengths and visible light, which cause most of the pigmentation. Hence a broad spectrum sunscreen with both UV and visible light protection is most useful in this condition. , The minimum level of UVA protection factor (UVAPF) has been set at a standard of at least one-third of the sun protection factor (SPF), hence a SPF/UVAPF ratio <3 is a minimum for providing adequate sun protection. Also for Indians, minimum UVAPF required is 12-17 in winter and a maximum of 29-30 in summer.  Sunscreens in the visible light range usually contain absorbing pigments such as iron oxides. Therefore adding this component to sunscreens increases their photoprotection capacities.
In order to reach balanced sun protection, a combination of UV filters is, therefore, necessary. So while selecting UV filters, they should have different maximum absorbance peaks (UVB, short UVA, long UVA) to cover entire UV spectrum, have appropriate phases of sunscreen emulsion (lipophilic and hydrophilic), and the combination has to be photostable.  Two hourly applications between 8 am and 4 pm are recommended. The presently available sunscreen components are as given in [Table 1].
New technologies like sunspheres and microencapsulation are the new kids on the block. Sunspheres have polymer beads filled with water that do not absorb UV irradiation, but enhance effectiveness of the active sunscreen ingredients. Microencapsulation has active sunscreen ingredients entrapped within a silica shell making it inert and making it possible to combine incompatible sunscreen ingredients safely without loss of efficacy.
Hydroquinone (1,4 dihydroxybenzene)
It still remains the most prescribed bleaching agent globally and remains the gold standard for management of hyperpigmentation. High absorption from skin and exogenous ochronosis are anticipated side effects [Figure 2]. A peculiar side effect of guttate hypomelanosis can develop in melasma lesions with use of more than 2% hydroquinone (HQ). 4-methoxyphenol, 4-isopropylcatechol, 4-hydroxyanisole and N-acetyl-4-S-cysteaminylphenol are some of the HQ derivatives, which have been tried with reasonable success.
Over the last few years, milder steroids have been replaced by potent steroids in triple combinations. This has led to increased side effects. Facial skin becomes atrophied due to the regular use of steroids resulting in extreme sensitivity towards sun exposure. The atrophy also leads to appearance of increased area of involvement in melasma. Such facial skin also becomes intolerant to the commonly used drugs in melasma. Clobetasol and betamethasone among potent steroids, mometasone in the mid-range and hydrocortisone among low potent steroids are the commonly used topical steroids in various triple combinations. The potent steroids should not be used for more than 4 weeks, should preferably be tapered to low potent steroids which should also be stopped in another 2 months.
It is especially useful in photodamaged and darker skin. Tretinoin 0.025-0.1% and adapalene 0.1% are the preferred preparations. Tazarotene, all trans-retinoic acid and isotretinoin have also been used with no added advantage being found over tretinoin.
It reduces DNA synthesis, inhibits mitochondrial cellular energy production and results in direct cytotoxic effects on melanocytes.  An added advantage with azelaic acid is that it does not cause depigmentation in normal skin as it targets only hyperactive and abnormal melanocytes. This specificity to abnormal melanocytes is unique and so side effects are lesser.  It also reduces the production of free radicals thus reducing hyperpigmentation.  Head to head studies between HQ 4% and azelaic acid are very few. Few studies even claim better efficacy for azelaic acid but further reports on long series of cases are awaited. , HQ presently continues to be the gold standard. It is usually very well tolerated and rarely causes irritation on topical application. 
Kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one)
It acts by chelating the free portion (copper) of tyrosinase. This is brought about by reducing o-phenones to diphenols. In addition, it has antioxidant and photoprotective properties.  It is stable and used in concentrations of 1-4%.  It is generally preferred as a second line therapy due, its good safety profile and stability especially when other therapies are not tolerated. It can be used along with other topical medications as also peels. Adverse effects include contact dermatitis, irritation and erythema. Monopolar radio frequency with transdermal delivery of kojic acid has been recently found to be a good modality for therapy. 
This natural plant product acts by inhibiting tyrosinase and decreasing melanin formation. The hydrolyzed product of arbutin acts as a free-radical scavenger and is more effective in inhibiting tyrosinase than arbutin.  Its action is dose dependent and has lesser adverse effects than HQ. Recently a derivative of arbutin, namely deoxyarbutin has been developed by removing hydroxyl groups. It produces reversible lightening of skin by directly inhibiting tyrosinase 
Mequinol (4-hydroxyanisole, 4-methoxyphenol)
It is a derivative of HQ, acts by competitively inhibiting formation of melanin precursors. It is reportedly more effective than HQ with lesser side-effects.  It is available as 2% solution containing in addition 0.01% retinoic acid, though it is still not marketed in India.
0It is a phenolic compound, which acts as substrate for tyrosinase and inhibits its activity. It is reportedly more stable and less irritating than HQ. Improvement can be seen as early as 2-4 weeks. 
In addition to its antioxidant effect, it affects melanin production by converting dopaquinone to its reduced derivative DOPA. It inhibits free radical production as also absorption of UV rays. Vitamin C may also chelate copper ions thus blocking tyrosinase activity. The advantage of this 5% topical preparation is almost nil side effects.  Magnesium ascorbyl phosphate, a more stable ester is the most prominent among them and it also protects against UVB pigmentation.  Iontophoresis has been found to increase its penetration and efficacy.
A combination of alpha-tocopherol with ferulic acid which maintains tocopherol in stable state is another novel agent for melasma. 
Niacinamide is the active amide of niacin. It reduces pigmentation by preventing transfer of the melanosomes to keratinocytes.  It has however no effect on tyrosinase.
It is obtained from the root of Glycyrrhiza glabra, a herb. Glabridin and Liquiritin are derivatives of liquorice which have shown benefit. Glabridin in addition to tyrosinase inhibition also has anti-inflammatory properties.  It acts by dispersing melanin and removing epidermal stains.
They are natural polyphenolic chemicals with anti-inflammatory, antiviral, antioxidant and anticancer properties. Catechins with gallic acid, ellagic acid and aloesin are few such compounds. Ellagic acid is an antioxidant derived from certain plants like eucalyptus, green tea and strawberry. It suppresses melanogenesis by blocking tyrosinase and does not cause any damage in cells. 
It is a new oligosynthetic peptide which inhibits tyrosine. Containing 0.01% oligopeptide cream, 20% glycolic acid lotion, an antioxidant cleanser and physical sunscreen, it is found to accelerate clearance in mild to moderate melasma. A study revealed improvement in facial melasma and clearance in just 6 weeks. 
It is a structural analog of vitamin A, which acts as agonist to vitamin A, saturates melanocyte receptors and reduce melanin production. It requires a prolonged duration of treatment but has few side effects.
A derivative of resorcinol, it inhibits TRP-1 in addition to tyrosinase and thus provides added benefit. 
It is another monounsaturated dicarboxylic acid mainly derived by biofermentation of oleic acid. It interferes with melanin synthesis by binding agonistically to nuclear peroxisome receptor which thereby regulates tyrosinase transcription and inhibits melanosome transfer.  1% dioic acid for 12 weeks is giving good results in few studies.
The topical plasmin inhibitor tranexamic acid in a 5% base is presently being studied in various countries with good initial successful reports.  Intralesional preparation of 0.05 ml (4 mg/ml) at weekly intervals for 12 weeks is a safe and effective mode of therapy according to latest studies. 
They act against tyrosinase, TRP-1 and TRP-2 at the molecular level by interacting with translation of targeted mRNA.
Methimazole is an oral antithyroid drug which has been recently discovered to have a depigmenting effect if used topically in a 5% preparation. A potent peroxidase inhibitor, it has been used to successfully treat melasma in few studies over a 6 week period, without affecting blood thyroid hormone levels. 
N-acetyl glucosamine, soybean extract, mulberry extract, thiotic acid, phenolic-thioether, cinnamic acid, pidobenzone, silymarin, 4-isopropylcatechol and linoleic acid with lincomycin.
The medical therapies are summarised in [Table 2].
| Combination Medical Therapy|| |
Kligman and Willis first popularised the combination of HQ 5%, tretinoin 0.1% and dexamethasone 0.1%.  Various modifications of this regime have been formulated over the decades. Gano and Garcia had used 2% HQ along with 0.05% tretinoin and in addition 0.1% betamethasone valerate.  Food and Drug Administration (FDA) had approved a modified Kligman's formulation which contains 0.05% tretinoin, 4% HQ and 0.01% fluocinolone acetonide. In a multicentric study performed in 569 subjects with moderate or severe melasma over 12 months, the melasma resolved in 80% subjects in 1 year.  Triple combination therapy takes 4 weeks to show significant improvement and 8 weeks for maximum results. These combinations are presently considered as the first line therapies in melasma.  However the FDA approved combination should not be used for more than 8 weeks continuously at a time.
Serial use of glycolic acid peels also significantly improves clinical efficacy of modified Kligman's formula. Glycolic acid in combination with HQ enhances the penetration of HQ. Other combinations include azelaic acid 20% with tretinoin 0.05 or 0.1%, azelaic acid 20%, HQ 4% and glycolic acid 20%, mequinol 2% with tretinoin 0.01%, HQ 2% and kojic acid 2% with glycolic acid 10% and mequinol 2% with 0.01% tretinoin.  Combinations of sunscreens with demelanising agents are also commonplace.
- Arbutin (deoxyarbutin) with aloesin act synergistically to inhibit melanin synthesis through combined competitive inhibition of tyrosinase, 
- Licorice extract with soy and ascorbic acid
- Kojic and phytic acid along with butyl methoxy-dibenzoyl methane
- HQ with kojic acid
- Combination of azelaic acid with HQ is found better than azelaic acid with glycolic acid
- Triple combination - Newer combinations containing 2% HQ, 1% mometasone and 0.025% tretinoin is also available. This combination should be used for not more than 4 weeks and is to be replaced by safer modalities. Presently a fluticasone based triple combination is now available in India as it is potentially safer than mometasone
- Hyalorunic acid in combination with HQ and glycolic acid. 
Pigmentary Disease Academy has recommended topical application of triple combination cream as the first line therapy in melasma.  Dual and monotherapies have slower onset of action and have lower efficacy. Hence they are recommended for use in patients intolerant to the triple therapy or wherein triple therapy is unavailable. Continuation of 2% HQ low dose as maintenance therapy is recommended.
| Systemic Medical Therapy|| |
Vitamin C was initially thought to be inhibiting tyrosinase, but was found to be ineffective. Proanthocyanidins also called condensed tannins, can be found in apples, pine bark, cinnamon, cocoa beans, grape seeds and red wine. Pycnogenol, the most prominent among them, obtained from bark of Pinus pinaster, a pine tree, is a powerful anti-oxidant. It is a more powerful antioxidant than vitamins C and E. Used at 75 mg/day, it protects against harmful effects of sun exposure.  They can be combined with vitamins A, C, and E as it protects them and also with tranexamic acid. Oral tranexamic acid is also showing satisfactory results in some studies though prolonged administration would be required. Significant side-effects in the form of visceral injury and coagulation problems may prevent its forward march.  Polypodium leucotomos, an extract of fern species, which contains polyphenols, are potent inhibitors of reactive oxygen species and also has anti-inflammatory and photo-protective properties. 
| Chemical Peels|| |
Glycolic acid, trichloraacetic acid (TCA) and salicylic acid are the peeling agents which have stood the test of time in the treatment of melasma. They are generally combined along with medical treatment for better and rapid clearance. They work well in epidermal and mixed variants of melasma. They are also helpful in the dermal variant by inducing inflammation and by helping macrophages in phagocytosing stagnant melanin.
Glycolic acid peels
They continue to be the most often used peels in melasma. 50-70% concentrations are the most commonly used. They are safe and are repeated once in 3-4 weeks for a minimum of 3-4 peels. Significant reductions in MASI has been achieved in 91% of subjects with epidermal forms responding better than mixed and dermal type not responding at all. Combination with medical therapy are useful in resistant cases when faster response is needed.
Trichloroacetic acid peel
Beginners usually should start at 10-15%. Concentrations upto 25% are usually used in Indian skin. TCA shows rapid but unpredictable response and has significant local reactions and relapse rate. Glycolic acid has slower onset, but incidence of local irritant reactions is lesser. Hence, TCA is better used initially to get rapid response followed by glycolic acid as maintenance.
Salicylic acid peel
Used in concentrations ranging from 15% to 30%, they can be applied at weekly to 2 weekly intervals for 4-6 sessions. However their efficacy in melasma is very low as compared to the role in acne. 
Effects are comparable to 70% glycolic acid.
Arginine, lactic acid, pyruvic acid and mandelic acid are newer peels which have better safety profile and are increasingly being used now-a-days. Lactic acid is a relatively cheaper and safer agent for chemical peeling. Full strength lactic acid solution (92%) has been found to be effective in few studies.  50% pyruvic acid, an alpha keto acid is also being used in few countries, but its unpredictability is a matter of concern.  Mandelic acid, a large molecule, penetrates epidermis very slowly and with uniformity and so is very good for patients with sensitive skin [Figure 3]. A lipophilic derivative of the salicylic acid, namely lipo-hydroxy acid, has newly been introduced. Used in concentrations of 5-10%, with a pH closer to normal skin pH and not requiring neutralization, it is likely to be a more popular agent in the future.  Tretinoin peels are left for 4-5 h before being washed away. Amino fruit acids are the latest in this group and they are still under evaluation.
|Figure 3: Treatment of melasma with newer mandelic acid peel: (a) Prepeel, (b) postpeel, (c) prepeel, (d) postpeel|
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Combination of peels
A combination of peeling agents enhances the depth of the peel without using a higher concentration of the peeling agent. However, these medium depth peels should be used cautiously in darker skinned patients because of the risk of uneven depth of peeling and increased risk of side effects, such as postinflammatory hyperpigmentation and scarring. The combinations include:
• Glycolic acid 70% combined with TCA 20%
• Solid carbon dioxide (CO 2 ) combined with 20% TCA
• Jessner's solution with 20% TCA.
Chemical peels can also be combined with other procedures for better effect:
• Chemical peeling combined with dermabrasion: This procedure was originally used by combining application of 50% TCA followed by dermabrasion for postacne scarring. The results and side effects are however debatable
• Chemical peeling can also be combined with laser resurfacing for skin rejuvenation
• Chemical peel with dermasanding using sandpaper, 
• Chemical peeling with botulinum toxin. 
| Dermabrasion|| |
Dermabrasion and microdermabrasion have been tried, but incidence of postprocedure hyperpigmentation precludes routine use. They are better utilized in refractory cases. Dermabrasion is also risky in dark skin due to chances of hyperpigmentation. 
| Platelet Rich Plasma|| |
The pigmentary improvement which occurs after platelet rich plasma (PRP) is probably more related to increase in the skin volume. Platelet derived growth factors found in PRP are involved in hyaluronic acid synthesis which increases skin tone and volume, thereby providing a more glowing skin with a feeling of reduced pigmentation.
| Laser and Light Sources|| |
Melanin has a broad absorption spectrum thereby allowing a variety of lasers and light sources to be used. Longer wavelengths penetrate deeper to ostensibly target dermal pigment, but melanin absorption is better with shorter wavelengths. However laser treatment is not recommended as the first line therapy due to high incidence of postinflammatory hyperpigmentation as also its modest efficacy.  Various lasers which may be of benefit are:-
Intense pulsed light
These light devices work over wavelengths of 515-1200 nm. They have shown moderately satisfying results in melasma refractory to topical therapy.  Cut-off filters with delivery of specific wavelengths and lower fluencies can reduce side effects. There is a downtime of 1-2 weeks and sessions are repeated every 3-4 weeks.
The QS ruby laser has been one of the earliest lasers tried in melasma. Chances of postinflammatory hyperpigmentation are high, and it is not considered presently as a good therapy. 1064 nm Q switch Nd:YAG (mode: Large spot size with low fluence) is emerging as a satisfactory new mode of therapy. Spot size: 6-8 mm diameter with energy: 400-900 mJ is considered ideal. The laser targets lesional melanocytes precisely by selective photothermolysis. It has the added advantage of being effective in the dermal aspect of melasma because of its deeper penetration.  Transient side-effects include wheals and purpura. Q switched alexandrite laser penetrates deeper and is hence useful in dermal melasma. Ultrapulse CO 2 to remove epidermal pigmentation followed by alexandrite has also been tried. However, the similar problem of postinflammatory pigmentary alteration precludes its routine use. 
Copper bromide lasers
The 511 nm wavelength which emits a green beam having fluences of 12-14 J/cm 2 can be utilized in the treatment of pigmentary lesions. The vascular etiology of melasma is given credence by this lasers effectiveness. Spot sizes of 1 mm, emission time of 50-60 ms, frequency of 7.7-8.3 pulses/s and 4 passes are considered ideal settings. The advantage with this laser is that melanin absorbs this spectrum to much greater extents leading to more selective damage. The thermal destruction is also restricted to only melanin containing epidermis. It is best when used in cases associated with telangiectasia. Approximately 10% cases report transient hyperpigmentation. 
Erbium YAG and CO 2 are not preferable for skin Types IV to VI due to high chances of scarring and postprocedure pigmentary changes.  Combination of erbium: YAG laser (2940 nm) with glycolic acid peels has been shown to improve refractory melasma after 6 months. However these methods are risky due to the pigmentary problems postprocedure.
Nonablative fractional resurfacing
This is a new method of treatment in melasma. Transdermal elimination of melanophages takes place with lesser postinflammatory hyperpigmentation. Improvements to the tune of 80% have been registered 26-28 weeks after one session of fractional photothermolysis. Energy settings between 6 mJ and 8 mJ with a density setting of 250 MTZs/cm 2 with total density of 2000 MTZ/cm 2 is usually the ideal setting.  Three treatment passes are used with one third horizontal and vertical overlap. It is useful in therapy resistant cases. Sessions can be repeated 3 weekly with improvement marked at 6 months postprocedure. Initial erythema for 2 days, followed by hyperpigmentation of 3-4 days, is the usually observed side effect. 60% of patients reported 75-100% clearances in a study on fractional lasers in melasma.  The limitations are mainly in darker skin where efficacy and improvement are limited and recurrence rates are high.
Fractional 1550 nm erbium-doped fiber restores lasers
The wavelength of 1550 nm allows penetration in dermis up to 300-1400 μm depth leading to benefits in the treatment of dermal and mixed melasma.  Energy of 6-12 mJ with once in 4 week sessions for 4 sessions is the average duration of prescription.
Q switch fractional ruby laser
This new modality with wavelength of 694 nm, pulse width of 40ns and spot size of 7.1 mm × 7.1 mm is being used successfully in certain centers. Fluences of 2-3 J/cm 2 with 6 sessions at 2 week intervals covering the whole face 3 times per session is found ideal for this therapy. This wavelength is more strongly absorbed and is definitely more selective for melanin than the similar Nd:YAG variant and should therefore be more useful in the times to come. It is however not a popular laser in India.
The pulse dye laser (PDL) is an emerging modality as of now.  Its use in melasma is based on the theory that vascularity and expression of VEGF receptors play an important role in pathogenesis of melasma. PDL targets the vascular component in melasma lesions, thereby decreasing melanocyte stimulation and probably even the subsequent relapses. Some initial studies are showing a positive beneficial response. 
1927 nm wavelength thulium laser
Thulium laser is the latest on the horizon and is found to offer good results. 
May provide better relief. The 950 μ/s pulsed CO 2 laser in one pass at 300 mJ/cm 2 decreases the hyperpigmentation by removing the entire epidermis and destroying melanocytes. Following this, the application of Q switched alexandrite laser at 6 J/cm 2 can target dermal melanin.  These are still not popular in this part of the world. Oral tranexamic acid in combination with the Q switched lasers is also proving to be beneficial.
This is a very recent method wherein collimated, low fluence, Q-switched Nd:YAG 1064 nm laser is being used with good results. This treatment reduces thermal damage by using top hat beam mode, shorter pulse width, higher peak power and lower fluence. 5-7 ns pulses with 7 mm spot size and 1.6-2.0 J/cm 2 fluences weekly for 8 weeks and two passes per treatment session have been found to be ideal. Triple cream combination either before or after the Laser therapy adds on to the benefits. 
Performing a test spot is advised before any laser procedure. Premedication with HQ for 4 weeks and antiviral prophylaxis against herpes simplex are also advocated. Addition of chemical peels reduces the hyperpigmentation and improves efficacy of lasers.
Lasers do not alter the basic pathomechanisms of melasma namely genetic influences, sun exposure and hormonal factors. Lasers rarely give reproducible and long standing improvement and recurrence almost always occurs. The high cost and risk of adverse effects place them as second line therapies for melasma. Medical management and chemical peels should ideally go hand in hand along with the laser therapy. An algorithm for management of melasma is given in [Table 3].
| Quality of Life in Melasma|| |
Quality of life in melasma can be assessed by the MELASQOL, an instrument consisting of a 10 question scale, on which patients are assessed on each question by a rating from 1 to 7 based on the Likert scale. Questions were based on physical, emotional, social and financial well-being. Scores range from 7 to 70 with higher scores indication worse quality of life.  The other indices which can be used include DLQI, SKINDEX-16 and HRQoL.
| Conclusion|| |
Treatment of melasma is very challenging. The relapsing tendency, dermal component which is difficult to treat and emotional swings associated with the condition are definite parts of the challenge. Strict sun protective measures by regular usage of sunscreens do offer some protection against relapse, but it is not absolute. So, treatment regimens must offer prolonged remission and in addition have to be safe to use for that prolonged period. Combination of HQ with topical tretinoin and steroids is considered first line therapy. Many new agents have been developed, though none have been ratified by controlled clinical trials. Dermal pigmentation however will take longer to regress than epidermal pigmentation as no therapy is generally effective in removing the dermal pigment. But treatment shouldn't be withheld even if there is a preponderance of mainly dermal pigment as the source of this pigment is also the epidermis, and even if epidermal melanogenesis can only be inhibited for prolonged periods, dermal pigment will not be replenished and will usually slowly resolve. Indian skin being darker and also being exposed to strong sunlight compounds the problem. So deep peels, are to be definitely avoided in Indians. Approach to treatment depends on type and severity of melasma.
| References|| |
Sivayathorn A. Melasma in orientals. Clin Drug Invest 1995;10:34-40.
Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol 1995;131:1453-7.
Pathak MA, Fitzpatrick TB, Kraus EW. Usefulness of retinoic acid in the treatment of melasma. J Am Acad Dermatol 1986;15:894-9.
Grimes PE, Yamada N, Bhawan J. Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol 2005;27:96-101.
Kang WH, Yoon KH, Lee ES, Kim J, Lee KB, Yim H, et al.
Melasma: Histopathological characteristics in 56 Korean patients. Br J Dermatol 2002;146:228-37.
Kang HY, Suzuki I, Lee DJ, Ha J, Reiniche P, Aubert J, et al.
Transcriptional profiling shows altered expression of wnt pathway- and lipid metabolism-related genes as well as melanogenesis-related genes in melasma. J Invest Dermatol 2011;131:1692-700.
Torres-Álvarez B, Mesa-Garza IG, Castanedo-Cázares JP, Fuentes-Ahumada C, Oros-Ovalle C, Navarrete-Solis J, et al.
Histochemical and immunohistochemical study in melasma: Evidence of damage in the basal membrane. Am J Dermatopathol 2011;33:291-5.
Kim EH, Kim YC, Lee ES, Kang HY. The vascular characteristics of melasma. J Dermatol Sci 2007;46:111-6.
Kim EJ, Park HY, Yaar M, Gilchrest BA. Modulation of vascular endothelial growth factor receptors in melanocytes. Exp Dermatol 2005;14:625-33.
Bak H, Lee HJ, Chang SE, Choi JH, Kim MN, Kim BJ. Increased expression of nerve growth factor receptor and neural endopeptidase in the lesional skin of melasma. Dermatol Surg 2009;35:1244-50.
Kang HY, Hwang JS, Lee JY, Ahn JH, Kim JY, Lee ES, et al.
The dermal stem cell factor and c-kit are overexpressed in melasma. Br J Dermatol 2006;154:1094-9.
Maeda K, Naganuma M. Topical trans-4-aminomethyl cyclohexanecarboxylic acid prevents ultraviolet radiation- induced pigmentation. J Photochem Photobiol B 1998;47:136-41.
Kim NH, Lee CH, Lee AY. H19 RNA downregulation stimulated melanogenesis in melasma. Pigment Cell Melanoma Res 2010;23:84-92.
Carlson JA, Linette GP, Aplin A, Ng B, Slominski A. Melanocyte receptors: Clinical implications and therapeutic relevance. Dermatol Clin 2007;25:541-57, viii.
Pérez M, Sánchez JL, Aguiló F. Endocrinologic profile of patients with idiopathic melasma. J Invest Dermatol 1983;81:543-5.
Kanwar AJ, Dhar S, Kaur S. Treatment of melasma with potent topical corticosteroids. Dermatology 1994;188:170.
Kimbrough-Green CK, Griffiths CE, Finkel LJ, Hamilton TA, Bulengo-Ransby SM, Ellis CN, et al.
Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial. Arch Dermatol 1994;130:727-33.
Pandya AG, Hynan LS, Bhore R, Riley FC, Guevara IL, Grimes P, et al.
Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol 2011;64:78-83.e1.
Khunger N, Kandhari R. Dermoscopic criteria for differentiating exogenous ochronosis from melasma. Indian J Dermatol Venereol Leprol 2013;79:819-21.
Clarys P, Alewaeters K, Lambrecht R, Barel AO. Skin color measurements: Comparison between three instruments: The Chromameter (R), the DermaSpectrometer (R) and the Mexameter (R). Skin Res Technol 2000;6:230-38.
Kang HY, Bahadoran P, Suzuki I, Zugaj D, Khemis A, Passeron T, et al. In vivo
reflectance confocal microscopy detects pigmentary changes in melasma at a cellular level resolution. Exp Dermatol 2010;19:e228-33.
Ardigo M, Cameli N, Berardesca E, Gonzalez S. Characterization and evaluation of pigment distribution and response to therapy in melasma using in vivo
reflectance confocal microscopy: A preliminary study. J Eur Acad Dermatol Venereol 2010;24:1296-303.
Sheth VM, Pandya AG. Melasma: A comprehensive update: Part II. J Am Acad Dermatol 2011;65:699-714.
Mahmoud BH, Ruvolo E, Hexsel CL, Liu Y, Owen MR, Kollias N, et al.
Impact of long-wavelength UVA and visible light on melanocompetent skin. J Invest Dermatol 2010;130:2092-7.
Moyal D. Need for a well-balanced sunscreen to protect human skin from both Ultraviolet A and Ultraviolet B damage. Indian J Dermatol Venereol Leprol 2012;78 Suppl 1:S24-30.
Moyal D. The development of efficient sunscreens. Indian J Dermatol Venereol Leprol 2012;78 Suppl 1:S31-4.
Nguyen QH, Bui TP. Azelaic acid: Pharmacokinetic and pharmacodynamic properties and its therapeutic role in hyperpigmentary disorders and acne. Int J Dermatol 1995;34:75-84.
Halder RM, Richards GM. Topical agents used in the management of hyperpigmentation. Skin Therapy Lett 2004;9:1-3.
Lowe NJ, Rizk D, Grimes P, Billips M, Pincus S. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther 1998;20:945-59.
Baliña LM, Graupe K. The treatment of melasma 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol 1991;30:893-5.
Farshi S. Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma. J Cosmet Dermatol 2011;10:282-7.
Lynde CB, Kraft JN, Lynde CW. Topical treatments for melasma and postinflammatory hyperpigmentation. Skin Therapy Lett 2006;11:1-6.
Kahn V. Effect of kojic acid on the oxidation of DL-DOPA, norepinephrine, and dopamine by mushroom tyrosinase. Pigment Cell Res 1995;8:234-40.
Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg 1999;25:282-4.
Cameli N, Abril E, Mariano M, Berardesca E. Combined use of monopolar radiofrequency and transdermal drug delivery in the treatment of melasma. Dermatol Surg 2014;40:748-55.
Bang SH, Han SJ, Kim DH. Hydrolysis of arbutin to hydroquinone by human skin bacteria and its effect on antioxidant activity. J Cosmet Dermatol 2008;7:189-93.
Chawla S, deLong MA, Visscher MO, Wickett RR, Manga P, Boissy RE. Mechanism of tyrosinase inhibition by deoxyArbutin and its second-generation derivatives. Br J Dermatol 2008;159:1267-74.
Jarratt M. Mequinol 2%/tretinoin 0.01% solution: An effective and safe alternative to hydroquinone 3% in the treatment of solar lentigines. Cutis 2004;74:319-22.
Jimbow K. N-acetyl-4-S-cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma. Arch Dermatol 1991;127:1528-34.
Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double-blind randomized trial of 5% ascorbic acid vs 4% hydroquinone in melasma. Int J Dermatol 2004;43:604-7.
Kobayashi S, Takehana M, Itoh S, Ogata E. Protective effect of magnesium-L-ascorbyl-2 phosphate against skin damage induced by UVB irradiation. Photochem Photobiol 1996;64:224-8.
Ichihashi M, Funasaka Y, Ohashi A, Chacraborty A, Ahmed NU, Ueda M, et al.
The inhibitory effect of DL-alpha-tocopheryl ferulate in lecithin on melanogenesis. Anticancer Res 1999;19:3769-74.
Greatens A, Hakozaki T, Koshoffer A, Epstein H, Schwemberger S, Babcock G, et al.
Effective inhibition of melanosome transfer to keratinocytes by lectins and niacinamide is reversible. Exp Dermatol 2005;14:498-508.
Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res 1998;11:355-61.
Shimogaki H, Tanaka Y, Tamai H, Masuda M. In vitro
and in vivo
evaluation of ellagic acid on melanogenesis inhibition. Int J Cosmet Sci 2000;22:291-303.
Hantash BM, Jimenez F. Treatment of mild to moderate facial melasma with the Lumixyl topical brightening system. J Drugs Dermatol 2012;11:660-2.
Khemis A, Kaiafa A, Queille-Roussel C, Duteil L, Ortonne JP. Evaluation of efficacy and safety of rucinol serum in patients with melasma: A randomized controlled trial. Br J Dermatol 2007;156:997-1004.
Wiechers JW, Rawlings AV, Garcia C, Chesné C, Balaguer P, Nicolas JC, et al.
A new mechanism of action for skin whitening agents: Binding to the peroxisome proliferator-activated receptor. Int J Cosmet Sci 2005;27:123-32.
Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, Kim MY, et al.
Localized intradermal microinjection of tranexamic acid for treatment of melasma in Asian patients: A preliminary clinical trial. Dermatol Surg 2006;32:626-31.
Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, Nakakes A. Topical 5% tranexamic acid for the treatment of melasma in Asians: A double-blind randomized controlled clinical trial. J Cosmet Laser Ther 2012;14:150-4.
Kasraee B, Safaee Ardekani GH, Parhizgar A, Handjani F, Omrani GR, Samani M, et al.
Safety of topical methimazole for the treatment of melasma. Transdermal absorption, the effect on thyroid function and cutaneous adverse effects. Skin Pharmacol Physiol 2008;21:300-5.
Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol 1975;111:40-8.
Gano SE, Garcia RL. Topical tretinoin, hydroquinone, and betamethasone valerate in the therapy of melasma. Cutis 1979;23:239-41.
Torok H, Taylor S, Baumann L, Jones T, Wieder J, Lowe N, et al.
A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads. J Drugs Dermatol 2005;4:592-7.
Rendon M, Berneburg M, Arellano I, Picardo M. Treatment of melasma. J Am Acad Dermatol 2006;54:S272-81.
Sarkar R, Bhalla M, Kanwar AJ. A comparative study of 20% azelaic acid cream monotherapy versus a sequential therapy in the treatment of melasma in dark-skinned patients. Dermatology 2002;205:249-54.
Hori I, Nihei K, Kubo I. Structural criteria for depigmenting mechanism of arbutin. Phytother Res 2004;18:475-9.
Guevara IL, Werlinger KD, Pandya AG. Tolerability and efficacy of a novel formulation in the treatment of melasma. J Drugs Dermatol 2010;9:215-8.
Ortonne JP, Passeron T. Melanin pigmentary disorders: Treatment update. Dermatol Clin 2005;23:209-26.
Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic acid as a new therapeutic peeling agent in melasma. Dermatol Surg 2005;31:149-54.
Philips N, Smith J, Keller T, Gonzalez S. Predominant effects of Polypodium leucotomos on membrane integrity, lipid peroxidation, and expression of elastin and matrixmetalloproteinase-1 in ultraviolet radiation exposed fibroblasts, and keratinocytes. J Dermatol Sci 2003;32:1-9.
Kodali S, Guevara IL, Carrigan CR, Daulat S, Blanco G, Boker A, et al.
A prospective, randomized, split-face, controlled trial of salicylic acid peels in the treatment of melasma in Latin American women. J Am Acad Dermatol 2010;63:1030-5.
Berardesca E, Cameli N, Primavera G, Carrera M. Clinical and instrumental evaluation of skin improvement after treatment with a new 50% pyruvic acid peel. Dermatol Surg 2006;32:526-31.
Taylor CR, Anderson RR. Ineffective treatment of refractory melasma and postinflammatory hyperpigmentation by Q-switched ruby laser. J Dermatol Surg Oncol 1994;20:592-7.
Uhoda E, Piérard-Franchimont C, Piérard GE. Comedolysis by a lipohydroxyacid formulation in acne-prone subjects. Eur J Dermatol 2003;13:65-8.
Khunger N. Standard guidelines of care for chemical peels. Indian J Dermatol Venereol Leprol 2008;74:S15-2.
Kunachak S, Leelaudomlipi P, Wongwaisayawan S. Dermabrasion: A curative treatment for melasma. Aesthetic Plast Surg 2001;25:114-7.
Li YH, Chen JZ, Wei HC, Wu Y, Liu M, Xu YY, et al.
Efficacy and safety of intense pulsed light in treatment of melasma in Chinese patients. Dermatol Surg 2008;34:693-700.
Manaloto RM, Alster T. Erbium: YAG laser resurfacing for refractory melasma. Dermatol Surg 1999;25:121-3.
Angsuwarangsee S, Polnikorn N. Combined ultrapulse CO2 laser and Q-switched alexandrite laser compared with Q-switched alexandrite laser alone for refractory melasma: Split-face design. Dermatol Surg 2003;29:59-64.
Lee HI, Lim YY, Kim BJ, Kim MN, Min HJ, Hwang JH, et al.
Clinicopathologic efficacy of copper bromide plus/yellow laser (578 nm with 511 nm) for treatment of melasma in Asian patients. Dermatol Surg 2010;36:885-93.
Zhou X, Gold MH, Lu Z, Li Y. Efficacy and safety of Q-switched 1,064-nm neodymium-doped yttrium aluminum garnet laser treatment of melasma. Dermatol Surg 2011;37:962-70.
Tannous ZS, Astner S. Utilizing fractional resurfacing in the treatment of therapy-resistant melasma. J Cosmet Laser Ther 2005;7:39-43.
Rokhsar CK, Fitzpatrick RE. The treatment of melasma with fractional photothermolysis: A pilot study. Dermatol Surg 2005;31:1645-50.
Naito SK. Fractional photothermolysis treatment for resistant melasma in Chinese females. J Cosmet Laser Ther 2007;9:161-3.
Passeron T. Long-lasting effect of vascular targeted therapy of melasma. J Am Acad Dermatol 2013;69:e141-2.
Passeron T, Fontas E, Kang HY, Bahadoran P, Lacour JP, Ortonne JP. Melasma treatment with pulsed-dye laser and triple combination cream: A prospective, randomized, single-blind, split-face study. Arch Dermatol 2011;147:1106-8.
Niwa Massaki AB, Eimpunth S, Fabi SG, Guiha I, Groff W, Fitzpatrick R. Treatment of melasma with the 1,927-nm fractional thulium fiber laser: A retrospective analysis of 20 cases with long-term follow-up. Lasers Surg Med 2013;45:95-101.
Nouri K, Bowes L, Chartier T, Romagosa R, Spencer J. Combination treatment of melasma with pulsed CO2 laser followed by Q-switched alexandrite laser: A pilot study. Dermatol Surg 1999;25:494-7.
Jeong SY, Shin JB, Yeo UC, Kim WS, Kim IH. Low-fluence Q-switched neodymium-doped yttrium aluminum garnet laser for melasma with pre- or post-treatment triple combination cream. Dermatol Surg 2010;36:909-18.
Balkrishnan R, McMichael AJ, Camacho FT, Saltzberg F, Housman TS, Grummer S, et al.
Development and validation of a health-related quality of life instrument for women with melasma. Br J Dermatol 2003;149:572-7.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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