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Indian Journal of Dermatology, Venereology, and Leprology, Vol. 77, No. 5, September-October, 2011, pp. 552-564 Review Article Facial melanoses: Indian perspective Neena Khanna, Seemab Rasool Department of Dermatology and Venereology, All India Institute of Medical Sciences, 1AYUSH, Ministry of Health and Family Welfare, Regional Research Institute of Unani Medicine, New Delhi, India Correspondence Address: Code Number: dv11165 DOI: 10.4103/0378-6323.84046 ABSTRACT Facial melanoses (FM) are a common presentation in Indian patients, causing cosmetic disfigurement with considerable psychological impact. Some of the well defined causes of FM include melasma, Riehl's melanosis, Lichen planus pigmentosus, erythema dyschromicum perstans (EDP), erythrosis, and poikiloderma of Civatte. But there is considerable overlap in features amongst the clinical entities. Etiology in most of the causes is unknown, but some factors such as UV radiation in melasma, exposure to chemicals in EDP, exposure to allergens in Riehl’s melanosis are implicated. Diagnosis is generally based on clinical features. The treatment of FM includes removal of aggravating factors, vigorous photoprotection, and some form of active pigment reduction either with topical agents or physical modes of treatment. Topical agents include hydroquinone (HQ), which is the most commonly used agent, often in combination with retinoic acid, corticosteroids, azelaic acid, kojic acid, and glycolic acid. Chemical peels are important modalities of physical therapy, other forms include lasers and dermabrasion. Key words: Corticosteroids, erythema dyschromicum perstans, facial melanosis, hydroquinone, lichen planus pigmentosus, melasma, Riehl's melanosis, retinoids Facial melanoses (FM), a common presentation of Indian patients, are complex diagnostic (and even greater therapeutic) problems consisting of few somewhat well defined clinical entities, several of which have overlapping features and some of which have defied classification [Table 1]. Most FM are commoner in darker races with both light and photosensitizing chemicals (occupational/ in cosmetics) playing an important role. Based on the location of melanin (as identified by color of lesion, accentuation of color under Wood’s light and histopathology, though the correlation between Wood’s lamp findings and histopathology is less than satisfactory) three types of hypermelanosis are identified:
MELASMA (CHLOASMA) Melasma is derived from Greek word melas (black) while chloasma is derived from the word chloazein (green), and since the pigmentation is brown-black, melasma is the preferred term.[1] Epidemiology Melasma is commoner in constitutionally darker skin types being most common in people with light brown skins, especially in people of East and South East Asian and Hispanic origin who live in areas with intense solar ultraviolet radiation (UVR).[1] It is commoner in women than in men (9:1) and is rare before puberty, occurring most commonly in women of reproductive age. Etiology The exact etiology of melasma is not known but several factors have been implicated. UVR (UVA and UVB) and visible light cause peroxidation of lipids in cellular membranes, leading to generation of free radicals, which stimulate melanogenesis. Elevated levels of estrogens and progesterone (as occurring in pregnancy) are important. Melasma also develops with estrogen- and progesterone-containing pills used for prostatic cancer.[2] However, progesterone may be more important, as melasma develops in postmenopausal woman who are given progesterone and not when given estrogen supplementation. Estrogens probably stimulate melanogenesis through estrogen receptors present on melanocytes.[1] Other hormones may also be important. Melasma is several times commoner in patients with thyroid disease than in controls and MSH may be important as melasma frequently begins as well as worsens during pregnancy as also after profound emotional stress. Pathogenesis The number of melanocytes in the lesions may be normal[2] or increased.[3] Melanosomes both within melanocytes and keratinocytes are increased in size probably due to increased expression of α-MSH in keratinocytes and overexpression of stem cell factor in fibroblasts and its receptor C-kit in melanocytes of involved skin.[4,5] Clinical features Melasma is characterized by symmetrical hyperpigmented macules [Figure 1], which may be blotchy, irregular, arcuate, or polycyclic and rarely have a linear or a starburst distribution. Depending on the location of melanin (vide supra), melasma is classified into:[6]
The face is most commonly affected though rarely pigmentation may extend on to V of the neck or may be confined to the forearms.On the face, three patterns of melasma are recognized:
Course Depending on the natural history of the lesions, melasma may also be classified into: • Transient type: which disappears within a year of withdrawal of hormonal stimulus. • Persistent type: which persists for more than a year after withdrawal of hormonal stimulus and is maintained by UVR and other factors. ERYTHEMA DYSCHROMICUM PERSTANS Syn: Ashy dermatosis of Ramirez,erythema chronicum figuratum melanodermicum.[8] Although Ramirezfirst described what is today labelled EDP, it is Sulzberger who is credited with coining the [8] term EDP. Epidemiology Though EDP has been reported from many countries including India,[9] it is most common in Latin America and Asia. It occurs in both sexes, but causes greater concern in women. Though it can affect any age group, characteristically lesions start in the 1st-2nd decade of life. Etiology The etiology of EDP is unknown, but anecdotal reports have incriminated exposure to ammonium nitrite, radiographic contrast media and chlorothalonil, intestinal whipworm infestation, cobalt allergy and HIV infection. In Mexican Mestizo patients, HLA-DR4 is associated with a genetic susceptibility to develop EDP. The relation of EDP to lichen planus (LP) is uncertain, both have several clinical, histological, and immunohistochemical similarities and often coexist[10] making some authors consider EDP a variant of LP.[11] The pigmentation in EDP is due to presence of melanin in the melanosome complexes in dermis (frequent) and in epidermis (sometimes). Clinical features EDP presents as numerous asymptomatic, gradually enlarging and coalescing, persistent, macules of variable sizes. Initially having an erythematous hue and an elevated dusky border (not always noted), lesions eventually become pigmented. Initially localised, lesions eventually cover extensive areas of face, trunk, and limbs. Pathology Under light microscopy (LM), there is vacuolar basal cell degeneration (BCD) with pigment incontinence (PI) and dermal melanophages and perivascular sleeve of lymphohistiocytic infiltrate at the active border while in the central pigmented area, there is increased epidermal pigmentation, PI, melanophages, and perivascular lymphohistiocytic infiltration. Ultrastructural studies have demonstrated melanosome complex-containing vacuoles within the cytoplasm of the basal and suprabasal keratinocytes with direct immunofluorescence show IgM cytoid bodies. LICHEN PLANUS PIGMENTOSUS Etiology and pathogenesis Though the exact etiology of lichen planus pigmentosus (LPP) is not known, cosmetics including fragrances, hair dyes, and mustard oil have been incriminated.[11] Clinical features LPP is characterized by generally asymptomatic (sometimes itchy), diffuse (less frequently reticular, blotchy, or perifollicular) hyperpigmented dark-brown to slate-grey to black macules [Figure 2] present mostly over exposed areas and flexures. The lesions lack the erythematous border of EDP. The clinical association of this entity with lesions of classical LP in about a third of patients and demonstration of colloid bodies on histopathology prompted Bhutani et al.,[12] to consider LPP a macular variant of LP and very similar to EDP. Though the mucous membranes are characteristically spared, some patients may have LP-like lesions. RIEHL’S MELANOSIS Syn: Pigmented cosmetic/ contact dermatitis Etiology Riehl’s Melanosis (RM) is probably a pigmented contact dermatitis (CD) to antigens present in cosmetics and textiles with anecdotal reports of air borne CD to musk ambrette and other plants.[13,14] Cosmetic allergens, include red and yellow pigments, chromium hydroxide, aniline and azo dyes, bactericidal agents (carbanilides, ricinoleic acids), hair dyes, red kumkum,[15] and fragrances. Textile allergens include optical whiteners, dyes, textile finishes, mercury compounds, formaldehyde, and rubber components. Sometimes occupational allergens like coal tar, pitch, asphalt, mineral oil, and chromates have been incriminated.[16] Pathogenesis Repeated contact with low levels of allergens (present in cosmetics and textiles) produces a type IV cytolytic reaction characterized by vacuolar BCD and PI rather than a frank eczematous reaction.[17] UV exposure may contribute in some, since pigmentation is often photo-localized and some of the chemicals implicated not only stimulate melanogenesis but are known photosensitizers. Epidemiology Incidence of RM is not known and though most reports are from Japan, cases have been reported from Europe, South America, India, and South Africa. In general, it is most pronounced in darkly pigmented races. Women appear to have a greater predilection, with majority of patients being young-middle aged women. Clinical features RM is characterized by diffuse/patchy/ rarely reticular pigmentation, often with satellite perifollicular pigmented macules and scaly follicular hyperkeratosis. Pigmentation is brown (almost black on the forehead and temples of dark skinned patients). It is sometimes preceded by mild erythema (often imperceptible in dark skinned) and pruritus. Sites of involvement depend on the allergen responsible – lesions due to cosmetics begin on forehead and temples spreading to involve rest of the face, even the chest, neck, scalp, hands, and forearms, while those due to textiles more often involve anterior aspect of thighs and axillae (sparing the vault).[18] Patients may show positive patch test to cosmetics or their ingredients.[19] Pathology LM of early lesions shows BCD, PI, and perivascular or band-like dermal infiltration, while older lesions show upper dermal melanophages. ERYTHROSE PERIBUCCALE PIGMENTAIRE DE BROCQ [EPP] Epidemiology Middle aged women are most frequently affected.[20] Etiology Photodynamic substances in cosmetics are probably responsible. A similar hyperpigmentation has been reported in patients with subsiding perioral dermatitis due to topical steroids.[21] Clinical features EPP is characterized by diffuse brown-red pigmentation present symmetrically around the mouth, with sparing the vermillion border. It may extend to the forehead, temples, and angles of the jaw. The erythema may fluctuate but pigmentation is persistent unless the cause is eliminated when it may fade very gradually. POIKILODERMA OF CIVATTE Epidemiology Though rarely reported, milder disease is probably not uncommon. It occurs predominantly in middle-aged women.[22] Etiology Photodynamic substances in cosmetics may be important. Clinical features It is characterized by the presence of reddish-brown reticulate pigmentation, telangiectasia and atrophy in irregular, symmetrical patches on the convexities of cheeks and the sides of the neck, sparing the area under the chin. ERYTHROMELANOSIS FOLLICULARIS OF FACE AND NECK [EF] Epidemiology and etiology Mainly reported in Japanese, EF is also not uncommon in Whites. Though mainly affecting young and middleaged men, it is also seen in adult females. Its cause is unknown.[23-25] Clinical features EF manifests as gradually progressive reddish-brown pigmentation and telangiectasis surmounted with pale, tiny follicular papules from which vellus (not terminal) hairs are lost [Figure 3]. The pigmentation involves periauricular areas sometimes, extending to the side of neck. Pathology The lesions are characterized by enlargement of sebaceous glands and hair follicles with the latter containing lamellar horny masses. The overlying flattened epidermis contains excess melanin and there is an inconspicuous lymphocytic infiltrate around dilated vessels. NEVUS OF OTA Syn: Oculodermal melanocytosis Epidemiology Nevus of Ota (NOO) is more common in Japanese, in women (9 times) with onset either in the perinatal period (50%) or around puberty (30%).[26] Etiology Due to racial differences, genetic factors are thought to be important but familial cases are rare. Pathogenesis NOO represents aborted embryonic migration of melanocytes from neural crest to epidermis. Late pubertal onset is explained by pigmentation of the amelanotic nevoid cells present at birth by adolescent spurt of sex hormones. Clinical features NOO is characterized by speckled or mottled coalescing blue-grey pigmentation of the area supplied by ophthalmic and maxillary divisions of trigeminal nerve. It is usually unilateral (90%). In addition to skin, pigmentation of NOO may involve oral mucosa and the eye (conjunctiva, sclera, retrobulbar fat, cornea, and retina) in which two levels of pigmentation - brown of conjunctiva and blue of sclera (often not overlapping) are clearly discernable. Based on the extent, NOO is classified into:
Variants Hori nevus,[27] or acquired bilateral nevus of Ota like macules (ABNOM) is probably a distinct variant seen in Koreans and Japanese. Unlike NOO, it has a late onset in adulthood, spares the mucosae, and is clinically characterized by bilaterally symmetrical speckled or confluent brownish-blue or slate-grey pigmentation over the malar regions, temples, root of the nose, alae nasi, the eyelids, and forehead. In cases of ABNOM confined only to the malar area or forehead, diagnosis is difficult because it mimics the centrofacial type of melasma. Without careful examination of alae nasi, forehead, and eyelids, brown ABNOM looks just like melasma, though histologically, fusiform-elongated dendritic melanocytes and melanophages are scattered among collagen bundles. The differentiation is essential because both are treated differently- melasma with topical agents while ABNOM with lasers. Course Though NOO persists, is only rarely complicated by melanoma and is anecdotally associated with ipsilateral glaucoma. PERIORBITAL MELANOSIS Periorbital melanosis (POM) (or dark circles) is an illdefined entity of great cosmetic concern.[28] Etiology Factors incriminated in etiology of POM include dermal melanin deposition, post inflammatory hyperpigmentation (atopic or contact allergic dermatitis), shadowing from lax skin, and infraorbital swelling have been incriminated. Familial periorbital hyperpigmentation is determined by an autosomal dominant gene[29] and in one study POM was found to be an extension of pigmentary demarcation lines over the face (PDL-F).[30] Pigmentary demarcation lines (PDL), also known as Futcher’s lines or Voigt’s lines, are abrupt transition lines from areas of deeper pigmentation to areas with less pigmentation. These are most often observed in darker races and are considered to be normal variants of pigmentation Clinical features POM is characterized by variegated brown to almost black discoloration around the eyes. ADDISON’S DISEASE Another cause of FM is Addisonian pigmentation.[31,32] Etiology Addisonian pigmentation typically occurs in primary adrenal insufficiency due to autoimmune adrenalitis, tuberculosis or other granulomatous diseases, metastatic malignant disease, sarcoidosis, amylodosis, and congenital adrenal hypoplasia. Pathogenesis Excessive production of ß-MSH and ACTH by the pituitary due to low circulating levels of adrenocortical steroids Pathology It is epidermal melanotic hyperpigmentation. Clinical features The pigmentation is most pronounced on the light exposed areas, flexures (e.g., axillae and fossae), palmar and plantar creases, areas subjected to repeated friction, the normally pigmented sites (e.g., nipples and genitalia) and mucous membranes (buccal, conjunctival, and vaginal) less distinctive pattern of hyperpigmentation may sometimes be observed. Pigmentation is minimal, if Addison’s disease develops rapidly. EXOGENOUS OCHRONOSIS Exogenous ochronosis (EO), a rare complication of hydroquinine (HQ), develops after prolonged use of high concentrations in dark-skinned patients and rapidly after use of even 2% in white-skinned.[33] It presents with diffuse pigmentation,[34] which under high magnification especially when using polarized light, is characterized by tiny, less than 1-mm sooty blue macules in a reticulate pattern.[35] Lesions are present in the HQ-treated photo-exposed areas viz cheeks, forehead and temporal and periorbital skin with less frequent involvement of nasal, peribuccal, and chin areas. Biopsy shows banana-shaped yellowbrown granules in and around collagen bundles along with giant cells and melanophage rich granulomas. Improvement occurs only very slowly (if at all) on withdrawal of HQ. POST CHIKUNGUNYA PIGMENTATION Epidemiology Since 2005, there is an ongoing outbreak of chikungunya in India.[36] Etiology Chikungunya is caused by alpha virus and is transmitted by Aedes aegypti and Aedes albopictus. Pathogenesis The exact cause of cutaneous manifestations in chikungunya fever is not known. Biopsy from hyperpigmented lesions shows an intact basal layer with diffuse hypermelanosis of the entire epidermis, suggesting an increased intraepidermal melanin dispersion/retention triggered by the virus. Clinical features Though the most common cutaneous manifestation of chikungunya is an erythematous maculopapular rash. An asymptomatic, brownish-black pigmentation, predominantly involving the centrofacial area, in form of freckle-like macules or slate-colored pigmentation is not uncommon. This may persist for about threesix months after the infection. Other patterns of pigmentation observed include melasma-like pigmentation over the face, periorbital melanosis, and a flagellate pattern of pigmentation on the face and extremities. ACANTHOSIS NIGRICANS Acanthosis nigricans is characterized by hyperpigmented, velvety plaques of body folds may also involve the face as well. Symptomatic treatments include topical retinoids and keratolytics.[37] DIAGNOSIS Some of the well-defined causes of FM include melasma, RM, LPP, EDP, and EPP and poikiloderma of Civatte. However, it is not possible to slot all patients into these clinical entities due to overlap in features. In case of any unexplained hyperpigmentation, evaluation of adrenal function is essential. TREATMENTFM causes cosmetic disfigurement with significant emotional impact.[38-41] Its treatment includes removal of provoking factors, vigorous photoprotection, and some form of active pigment reduction either with topical agents or physical modes of treatment. There is no universally effective specific therapy — existing agents have varying degrees of efficacy and relapses are frequent.[38] Photoprotection Photoprotection is essential, because photodarkening can occur with just a couple of hours of sun exposure.[1] Life style modification This entails avoiding peak hours of sunlight (in tropics, between 11 AM - 4 PM), using shady side for activities and making use of sunshades like parasols and broad rimmed hats. Sunscreens Opaque sunscreens containing zinc oxide, 10% (and SPF of 30) have dual benefit of camouflaging FM and preventing photo-induced darkening. Addition of benzophenones has added benefit. Avoidance of provoking factors Avoiding triggers is necessary in melasma, RM, and other causes of FM Lightening agents Topical agents need to be used for several months before effect becomes apparent[39] and are much more effective when pigment is epidermal. Hydroquinone Hydroquinone (HQ), used alone or in combination, is the gold standard for the treatment of melasma and other FM, particularly of epidermal type. HQ inhibits tyrosinase (decreasing conversion of DOPA to melanin) and so reduces formation and melanization of melanosomes. It also promotes degradation of melanosomes and destruction of melanocytes.[40] The efficacy of HQ in FM depends on several factors. Epidermal pigmentation responds better than dermal. Higher concentrations give better results (4% being more effective than 2% and 6-10% prepared extemporaneously being effective even in resistant cases) with a hydroalcoholic solution being most effective. Used in concentration of 2−5%, the response in melasma becomes evident after 5−7 weeks and therapy needs to be continued for at least 3−12 months.[41] HQ has been combined with retinoic acid (RA) and fluocinolone acetonide (triple combination) or with 10% glycolic acid (GA) to improve its efficacy. Adverse reactions of HQ are “dose” and “duration of use” dependant. Acute reactions like asymptomatic transient erythema and dose dependent irritation are not uncommon but allergic CD and nail discoloration are infrequent. A confetti-like depigmentation may develop with concentrations higher than 2% as also with monobenzylether of HQ, which should never be used in melasma. A rare complication of HQ is exogenous ochronosis (vide supra). Use of HQ is banned in cosmetics in Japan, Europe, and USA, because of safety issues.[42] Being an oxidizing agent, HQ changes from white to brown and this needs to be discarded as it is ineffective.[43] Azelaic acid Azelaic acid (AA) is antiproliferative and cytotoxic to melanocytes. It is a weak competitive inhibitor of tyrosinase.[44] It also reduces production of free radicals. AA has been used for treatment of melasma and postinflammatory hyperpigmentation (PIH). In melasma, AA 20% is as effective as 4% and superior to 2% HQ, but without its side effects.[45] To hasten and improve response, AA has been combined with 0.05% RA or 15−20% GA.[46] However, combining with clobetasol propionate does not enhance its effect.[47] AA is generally well tolerated. Pruritus, mild erythema, and burning may develop but improve even on continuation of treatment. Phototoxic and allergic reactions are rare. Kojic acid Kojic acid (KA) inhibits production of free tyrosinase and is a potent antioxidant.[48] When used alone, KA, 1−4%, is only modestly efficacious. However, KA has a place as a combination therapy in management of FM, if the patient has difficulty tolerating other firstline therapies. A combination of KA, 2% and HQ, 2% is superior to combination of GA 10% and HQ 2%[49] and a combination of GA, 5% and KA, 4% was as effective in melasma as a combination of GA 5% and HQ 4% at 12 weeks.[50] KA may cause CD and erythema. Retinoids All topically available retinoids viz., retinoic acid RA, isotretinoin, adaplene and tazarotene have been used to treat melasma, either as monotherapy or combined with HQ, topical steroids and a host of other agents. Retinoids reduce hyperpigmentation by promoting loss of melanin through increased epidermal turnover, reducing transfer of melanosomes from melanocytes to keratinocytes by decreasing contact time and reducing melanogenesis by inhibiting tyrosinase transcription.[51] Used as monotherapy, 0.1% RA is more effective than 0.05% and 0.025%, but is also more irritating.[52] With isotretinoin the response is equivocal but in Indian patients, adapalene is as efficacious as RA but with significantly less irritation.[53] Though RA takes longer than HQ to act (clinically significant lightening evident only after 24 weeks), the response when combined with HQ (5%), and lactic acid (7%) or ascorbic acid (10%) is not only better but faster as well. Irritation is the commonest side effect and may even cause hyperpigmentation, particularly in darkskinned. It is more frequent with higher concentration of RA and less with adaplene. Photosensitivity is also not uncommon. Topical steroids Mechanism of skin-lightening with topical corticosteroids is ill-understood, but they inhibit synthesis of mediators like prostaglandin and leukotriene and this may partly explain their effect on melanogenesis. Though potent/superpotent steroids do reduce pigmentation of melasma,[54] monotherapy is best avoided due to frequent adverse effects. Steroids of different potencies have been combined (for synergistic effects and reducing irritation due to other products) with HQ (2−10%) and RA (0.025−0.1%) in treatment of melasma.[55] Disadvantages of topical steroids include rosacea-like dermatosis, atrophy, telangiectasia and hypertrichosis. Glycolic acid Glycolic acid (GA) acts in hyperpigmentation probably due to its effect on epidermal remodelling and accelerated desquamation, resulting in quick pigment dispersion. It also directly inhibits tyrosinase.[56] A combination of 10% GA and 4% HQ has been shown to have good clinical efficacy in treating melasma in Hispanic patients. Irritation is common and resolves with temporary withdrawal combined with application of moisturizers.[57] Lesser used agents Although experimental evidence suggests efficacy of a number of natural and synthetic agents in FM, dependable, controlled clinical trials are lacking. Most of these agents have been used in combinations and marketed as over-the-counter preparations. Niacinamide Niacinamide, an important component of the over the counter ‘fairness creams’ reduces pigmentation by reversibly preventing transfer of melanosomes from melanocytes to the keratinocytes without affecting the tyrosinase activity.[58] In clinical studies, niacinamide decreases hyperpigmentation compared with vehicle alone after 4 weeks of use.[59] Its efficacy is doubled by low-frequency sonophoresis, which enhances percutaneous absorption.[60] Mequinol Mequinol is a derivative of HQ. It acts as a competitive inhibitor reducing formation of melanin precursors. Though efficacious, controlled clinical trials are needed to establish its place in management of FM. In melasma, a 2% lotion used in combination with 0.01% RA (to enhance penetration), has been found superior to 3% HQ.[61] This combination resulted in complete clearance in 4 of the 5 patients with melasma at 12-weeks with all patients maintaining the improvement at 16-weeks.[62] In France, it is used in concentration of 8−10% in treatment of melasma and PIH. Side effects include irritation (reduced by using a sunscreen[63]), halo hypopigmentation and depigmentation both locally and at distant sites. Arbutin and deoxyarbutin Arbutin is a natural occurring derivative of HQ and deoxyarbutin is a dehydroxylated derivative of arbutin. Arbutin is hydrolysed in the skin by the flora to HQ and produces skin-lightening by direct, dose dependent inhibition of tyrosinase.[64] Although good controlled clinical trials are lacking, initial in vitro and in vivo experiments have demonstrated its safety and efficacy in hypermelanotic disorders.[65] Ascorbic acid Ascorbic acid (AsA) has antioxidant properties and reduces melanogenesis by inhibiting conversion of dopaquinone to DOPA. It also absorbs UVR, preventing free-radical production. Because of its instability in aqueous solution, esters like magnesium ascorbyl-2phosphate (MAP) with similar properties are used.[66] AsA can be used alone or in combination therapy. Though 5% AsA is less effective than 4%HQ in melasma, but it has a better safety profile.[67] MAP was found to significantly reduce pigmentation in 19 of 34 patients with melasma and senile freckles but only in 3 of 25 patients with normal skin.[68] A 25% L-ascorbic acid formulated with a penetration enhancer, was found to significantly improve melasma.[69] Liquorice derivatives Liquorice is root of the perennial herb Glycyrrhiza glabra. Glabridin and other oil-soluble derivatives of liquorice inhibit tyrosinase in vitro.[70] Liquiritin, another derivative, reduces skin pigmentation, but without inhibiting tyrosinase. A 20% liquiritin cream was found effective at 4 weeks in treatment of melasma.[71] Miscellaneous agents N-acetyl-4-S-cysteaminylphenol (NCAP) acts as an alternative substrate for tyrosinase, inhibiting its activity. In a retrospective analysis of 12 patients with melasma who used 4% NCAP, 66% showed marked improvement with the lightening being evident as early as after 2−4 weeks.[72] It is more stable and less irritant than HQ. Alpha-tocopheryl ferulate absorbs UVR and significantly retards melanogenesis, possibly by inhibiting tyrosine hydroxylase in an indirect manner. Flavonoids including catechin (from green tea leaves), ellagic acid (from green tea, strawberies, eucalyptus etc.), and aloesin (from aloe tree), are naturally occurring polyphenols, with antioxidant and hypopigmentary properties. Their role in FM is still being investigated. Other agents known to affect melanin pigmentation and sometimes used in formulations are N-acetyl glucosamine, thiotic acid (alpha-lipoic acid), gentisic acid, soybean extract, and paper mulberry extract. Combination treatment Topical agents act on different stages of melanogenesis, therefore when combined give better therapeutic results. Agents are also combined to reduce untoward effects e.g., topical steroids reduce irritation due to both HQ and retinoids and retinoids themselves counter steroid-induced atrophy. Some agents are used as “stabilizers” and hypomelanotic agents are often combined with sunscreens. HQ is the most commonly used agent, often being combined with GA, AA, KA, RA, or corticosteroids. The most extensively studied and widely used combination with HQ is with RA and corticosteroids- the “triple combination”. First proposed by Kligman and Willis,[73] the original combination contained 5% HQ, 0.1% tretinoin, and 0.1% dexamethasone and was found effective in melasma, ephelides, and PIH. Due to the irritation, the combination has been modified to reduce HQ to 2−4% and tretinoin to 0.025−0.05% and the steroid has been variously changed to fluocinolone acetonide or others. Due to its efficacy in clinical situations it is extensively used as first line therapy for melasma and other FM. Only when the triple combination is unavailable or when patients do not tolerate it, should other modalities be used. Physical therapies Chemical peels Chemical peels have been used to treat FM either as stand alone treatment or combined with other modalities. Epidermal melasma responds best and patients who continue topical therapy after the peel, maintain improvement better than those who do not.[74] Medium depth peels should be performed with great caution, especially in dark skinned patients and deep peels are not recommended for Indian skin because of high risk of prolonged or permanent pigmentary changes.[75] Side effects of chemical peels include erythema, stinging, exfoliation and post inflammatory hypo and hyperpigmentation. Used in concentration of 50−70%, a 91% reduction in MASI is seen with three peels of GA at monthly intervals.[76] The addition of 20% GA peels every 3 weeks marginally improves the response of moderate to severe melasma to combination of 10% GA and 2%HQ.[77] Addition of KA improves the response to GA peels.[78] Salicylic acid (SA), 20−30% peels used at 2-weekly intervals also results in moderate-significant improvement in 88% of patients with FM (including melasma). Similarly, RA, 1−5% peels at 2−3 days intervals has shown both clinical and histological evidence of improvement in melasma in patients with skin types I−IV.[79] Laser therapy Treatment of Nevus of Ota with lasers is extremely gratifying. QS Nd:YAG laser (wavelength 1064 nm) is the most widely used laser in darker skin types because longer wavelengths and a large spot size allows deeper penetration. Six to eight treatments at intervals of 2−6 months are necessary, with lightening seen even in between sessions. Temporary postinflammatory hyper and hypo pigmentation is frequent in Indian skin but can be minimized with good pre and postoperative care. Purpura and pin point bleeding occur at higher fluences or if smaller spot size is used.[80] In contrast, though anecdotally several lasers have been reported to be effective in patients with other causes of FH, they should not be the first line therapy (unpredictable response, frequent relapses despite initial improvement, risk of postinflammatory hyper and hypopigmentation). Lasers may, however, be used in selected resistant cases, after proper counselling and preferably after a test patch. A combination of pulsed CO2 laser (to remove epidermal pigment) and alexandrite laser (to remove dermal pigment) gives a better reduction in MASI than with either used alone.[81] Q-switched alexandrite laser has also been effectively used in other causes of FM in combination with 15−25% TCA and Jessner’s solution, with 67% of these patients maintaining the good-excellent response at 24 months.[82] Similarly Erbium: YAG laser (2.94µ m; at 5.1 to 7.6J/cm2) has been found effective women with melasma unresponsive to topical therapy and chemopeeling.[83] Q-switched ruby laser is ineffective in melasma. Dermabrasion Patients with resistant melasma especially with a prominent dermal component have been successfully treated with local or full-face dermabrasion upto upper or mid dermis using a 16-mm diameter coarse grit diamond fraise with 97% of the patients maintaining the improvement for a mean of 5 years. Less than 1% patients developed hypertrophic scars or permanent hypopigmentation.[84] Special situations It is best to defer treatment of melasma of pregnancy primarily because frequently disappears after delivery. Even if treated, it is resistant to treatment, due to persistent hormonal trigger. During pregnancy it is best just to advocate frequent application of a broad spectrum sun screen. CONCLUSION Management of FM is challenging requiring withdrawal of the ‘trigger’, vigorous use of sunscreens, an array of depigmenting agents of which HQ is considered gold standard. Although in vivo and in vitro studies have shown the efficacy of several other agents, their place in the management of FM is still not defined. For melasma, the consensus is that first line therapy should consist of effective topical therapies, mainly fixed triple combinations [Table 2]. Where patients have either sensitivity to the ingredients or a triple combination therapy is unavailable other compounds with dual ingredients (HQ plus GA) or single agents (4% HQ, 0.1% RA, or 20% azelaic acid) may be considered as an alternative. In patients for whom therapy has failed, options for second-line therapy include peels either alone or in combination with topical therapy. Most patients will require therapy to maintain remission status and a combination of topical therapies should be considered. Lasers should rarely be used in the treatment of melasma and, if applied, skin type should be taken into account. There are currently no guidelines for the management of other FM and given their heterogeneous nature and the variations of assessing treatment modalities, it is difficult to make effective comparisons between outcomes. REFERENCES 1. Bandyopadhyay D. Topical treatment of melasma. Indian J
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